Antiviral compounds highly effective as hcv-ns5a inhibitor

ABSTRACT

Provided are compounds antiviral compounds represented by formula Ia and Ib: 
     
       
         
         
             
             
         
       
     
     that are highly potent as HCV NS5A inhibitors, where the structural variables are as defined herein. These compounds are useful in, for example, inhibiting Hepatitis C virus and treating Hepatitis C virus infections.

DESCRIPTION OF THE BACKGROUND

The present application claims benefit of the filing date of Chinese patent application No. CN201310224756.X, filed on Jun. 6, 2013, incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to two classes of novel antiviral compounds, pharmaceutical compositions and their uses thereof as an effective HCV-NS5A inhibitor.

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) infection leads to chronic liver disease such as cirrhosis and hepatocellular carcinoma. Hepatitis C virus (HCV) is a single-stranded positive RNA virus in the Flaviviridae family. HCV includes a nucleocapsid protein (C), envelope proteins (E1 and E2), and several non-structural proteins (NS1, NS2, NS3, NS4a, NS5a, and NS5b), and it is known that the NS3 and NS5 (NS5A and NS5B) proteins are essential for viral replication. So far, HCV infection is one of the major infection diseases, and about 3-5% of the world's population was infected with HCV.

Currently, there were several new HCV NS5A inhibitors such as BMS-790052, IDX791 and GS-5885 reported in Phase I-III clinical trials in USA and Europe [Ref: WO2008/021927 A2, WO2010/132601 A1, WO2011/075615 A1]. The present invention is based on the discovery of two classes of novel antiviral compounds highly effective as HCV-NS5A inhibitor with excellent potency and safety.

SUMMARY OF THE INVENTION

The present inventor relates to two classes of novel antiviral compounds of the following formulas Ia-Ib with the polyaryl and heteroaryl core based structure, which has been evaluated to be highly potent and effective for inhibiting the NS5A replication of hepatitis C virus (HCV). This invention further relates to pharmaceutical compositions comprising one or more of new developed compounds (in a pure form or mixture of stereoisomers, solvates, hydrates, tautomers, prodrugs, or pharmaceutically acceptable salts thereof) and another agent(s) developed as therapeutic drugs for HCV treatment.

In the first aspect, the present invention provides a compound represented by the formula Ia or Ib, or a stereoisomer, tautomer, esterification or amidation prodrug or pharmaceutically acceptable salt thereof:

wherein:

m=1, 2 or 3;

n=1, 2 or 3;

each dashed line “

” is, independently, a single bond or double bond;

when “

” is a single bond, D and D¹ are each, independently, selected from the group consisting of O, S, N(Ra), CH₂, CH(OH), or C(Rb)(Rc);

Ra is H, C₁-C₂₀ hydroxy, alkyl, C₁-C₂₀ cycloalkyl, C₆-C₂₀ aryl, C₂-C₂₀ heteroaryl, C₁-C₂₀ alkoxycarbonyl, C₃-C₂₀ cycloalkyloxycarbonyl, C₆-C₂₀ aryloxycarbonyl, C₂-C₂₀ heterocycloalkyl-oxycarbonyl, C₁-C₂₀ alkylaminocarbonyl, C₃-C₂₀ cycloalkylaminocarbonyl, C₁-C₂₀ alkylamino sulfonamido, C₂-C₂₀ heterocycloalkyl-aminosulfonyl, or C₆-C₂₀ arylaminosulfonyl;

Rb and Rc are each, independently, selected from the group consisting of H, halogen, hydroxy, cyano, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₂-C₂₀ heterocycloalkyl, C₆-C₂₀ aryl, C₁-C₂₀ alkoxy, C₁-C₂₀ alkylthio, C₁-C₂₀ alkoxycarbonyl, C₆-C₂₀ aryloxy, C₆-C₂₀ heteroaryloxy, C₆-C₂₀ fused aryloxy, C₆-C₂₀ fused heterocycloalkyl-oxy, C₆-C₂₀ aryloxycarbonyl, C₂-C₂₀ heterocycloalkyl oxycarbonyl, C₂-C₂₀ heteroaryl, C₁-C₂₀ alkylamino, C₂-C₂₀ heterocycloalkylamino, C₆-C₂₀ arylamino, C₁-C₂₀ alkylaminocarbonyl, C₁-C₂₀ alkylcarbonylamino, C₁-C₂₀ alkylsulfonamido, C₂-C₂₀ heterocycloalkylsulfonamido, C₆-C₂₀ arylsulfonamido, and C₁-C₂₀ alkylaminosulfonamido;

or Rb and Rc may be linked to form a C₂-C₂₀ cycloalkyl, C₂-C₂₀ cycloalkenyl, or C₁-C₂₀ cycloethereal group;

when “

” is a double bond, D and/or D¹ are each, independently, selected from the group consisting of N, CH, and C(Rb), wherein the definition of Rb is the same as the Rb in D and D¹ above;

Ar, Ar¹, Ar² and Ar³ are each, independently, selected from the group consisting of C₆-C₂₀ aryl, C₂-C₂₀ heteroaryl, C₈-C₂₀ fused aryl, and C₄-C₂₀ fused heteroaryl.

or Ar and Ar¹ or Ar¹ and Ar² may be linked each other to form C₁₀-C₂₀ fused alkylaryl or C₈-C₂₀ aryl group,

or Ar¹ or Ar² does not exist and the groups bonded to Ar¹ or Ar² are directly linked;

E and G are each, independently, selected from the group consisting of N, CH and C(Rb); wherein the definition of Rb is the same as the Rb in D and D¹ above;

K is C₂-C₂₀ mono-heteroaryl, C₂-C₂₀ poly-heteroaryl, or C₂-C₂₀ fused-heteroaryl represented by one of the following structures:

L and L¹ are each, independently linked with D and/or D¹, selected from the group consisting of O, S, N(Ra), C(═O), C(═O)O, C(═S)O, and C(═O)N(Ra), wherein the definition of Ra is the same as the Ra in D and D¹ above;

-   -   or L and/or L¹ are not present:

Q and Q¹ are each, independently, selected from the group consisting of C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, C₁-C₂₀ alkylamino, C₃-C₂₀ cycloalkylamino, C₆-C₂₀ aryl, C₃-C₂₀ heteroaryl, C₃-C₂₀ poly-heteroaryl, C₃-C₂₀ fused aryl, and C₃-C₂₀ heteroaryl group, wherein when L and/or L¹ is not present, Q and/or Q¹ is not present;

W and W¹ are each, independently, selected from the group consisting of carbonyl, thiocarbonyl, C₁-C₂₀ alkyl, C₆-C₂₀ aryl, and C₂-C₂₀ heteroaryl group;

W² and W³ are each, independently, selected from the group consisting of carbonyl, thiocarbonyl, sulfonyl, C₁-C₂₀alkyl, C₂-C₂₀ heterocycloalkyl, C₆-C₂₀ aryl, and C₂-C₂₀ heteroaryl group;

Y and Y¹ are each, independently, selected from the group consisting of H, C₁-C₂₀alkyl, C₃-C₂₀ cycloalkyl, C₆-C₂₀ aryl, C₁-C₂₀ alkylcarbonyl, C₆-C₂₀ arylcarbonyl, C₂-C₂₀ heterocycloalkylcarbonyl, C₁-C₂₀ alkoxycarbonyl, C₁-C₂₀ cycloalkyl-oxy-carbonyl, C₆-C₂₀ aryloxycarbonyl, C₂-C₂₀ heteroaryloxycarbonyl, C₁-C₂₀alkylaminocarbonyl, C₁-C₂₀ alkylsulfonyl, C₃-C₂₀ cycloalkylsulfonyl, C₆-C₂₀ arylsulfonyl, C₁-C₂₀ alkylamino sulfonyl, C₃-C₂₀ cycloalkylaminosulfonyl, and C₆-C₂₀ arylaminosulfonyl group:

Z and Z¹ are each, independently, selected from the group consisting of H, hydroxy, amino, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₁-C₂₀ alkoxy, C₃-C₂₀ cycloalkyl-oxy, C₁-C₂₀ alkylamino, C₃-C₂₀ cycloalkylamino, C₂-C₂₀ heterocycloalkyl, C₂-C₂₀ heterocycloalkylamino, C₆-C₂₀ aryl, C₆-C₂₀ aryloxy, C₆-C₂₀ arylamino, C₃-C₂₀ heteroaryloxy, C₃-C₂₀ heteroarylamino, C₁-C₂₀ alkylsulfonamido, C₃-C₂₀ cycloalkylsulfonamido, C₆-C₂₀ arylsulfonamido, C₁-C₂₀ alkoxysulfonamido, C₃-C₂₀ cycloalkyl-oxy-sulfonamido, C₆-C₂₀ aryloxysulfonamido, C₁-C₂₀ alkylaminosulfonamido, C₃-C₂₀ cycloalkylaminosulfonamido, and C₆-C₂₀ arylaminosulfonamido group;

R¹, R², R³ and R⁴ are each, independently, selected from the group consisting of H, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₂-C₂₀ heterocycloalkyl, C₆-C₂₀ aryl, C₂-C₂₀ heteroaryl, C₁-C₂₀ alkoxycarbonyl, C₆-C₂₀ aryloxycarbonyl, C₂-C₂₀ heterocycloalkyl-oxy carbonyl, C₁-C₂₀ alkylaminocarbonyl, C₁-C₂₀ alkylaminosulfonamido, C₂-C₂₀ heterocycloalkylamino sulfonyl, and C₆-C₂₀ arylaminosulfonyl group;

R⁵, R⁶, R⁷ and R⁸ are each, independently, selected from the group consisting of H, halogen, hydroxy, cyano, amino, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₂-C₂₀ heterocycloalkyl, C₁-C₂₀ alkoxy, C₁-C₂₀ alkylamino, C₂-C₂₀ heterocycloalkylamino, C₆-C₂₀ aryl, C₃-C₂₀ heteroaryl, C₆-C₂₀ arylamino, C₁-C₂₀ alkoxycarbonylamino, C₁-C₂₀ alkylaminocarbonylamino, C₁-C₂₀ alkylsulfonamido, C₂-C₂₀ heterocycloalkylsulfonamido, C₆-C₂₀ arylsulfonamido, and C₁-C₂₀ alkylaminosulfonamido,

or R⁵ and R⁶ may be linked to each other to form a cyclo group,

or R⁷ and R⁸ may be linked to each other to form a cyclo group; and

R⁹, R¹⁰, R¹¹ and R¹² are each, independently, selected from the group consisting of H, halogen, hydroxy, cyano, amino, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₁-C₂₀alkoxy, C₁-C₂₀ alkylamino, C₂-C₂₀ heterocycloalkylamino, C₆-C₂₀ aryl, C₃-C₂₀ heteroaryl, C₆-C₂₀ arylamino, and C₁-C₂₀ alkoxycarbonylamino,

or the R⁹ and R¹⁰ may be linked to each other to form a cyclo or spiro group, and

the R¹¹ and R¹² may be linked to each other to form a cyclo or spiro group.

In a preferred embodiment of the invention, m=1 or 2 and n=1 or 2.

In another preferred embodiment of the invention, the dashed line “

” is double bond and D and/or D¹ are CH.

In another preferred embodiment of the invention:

the dashed line “

” is single bond:

D and D¹ are each, independently, selected from the group consisting of O, S, N(Ra), CH₂, CH(OH) and C(Rb)(Rc);

Ra is H, hydroxy, C₁-C₁₂ alkyl, C₁-C₁₂ cycloalkyl, C₆-C₁₂ aryl, C₂-C₁₂ heteroaryl, C₁-C₁₂ alkoxycarbonyl, C₃-C₁₂ cycloalkyloxycarbonyl, C₆-C₁₂ aryloxycarbonyl, C₂-C₁₂ heterocyclo-oxycarbonyl, C₁-C₁₂ alkylaminocarbonyl, C₃-C₁₂ cycloalkylaminocarbonyl, C₁-C₁₂ alkylaminosulfonamido, C₂-C₁₂ heterocycloaminosulfonyl, or C₆-C₁₂ arylaminosulfonyl; and the Rb and Rc are each, independently, selected from the group consisting of H, halogen, hydroxy, cyano, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₂-C₁₂ heterocyclo, C₆-C₁₂ aryl, C₁-C₁₂ alkoxy, C₁-C₁₂ alkylthio, C₁-C₁₂ alkoxycarbonyl, C₆-C₁₂ aryloxy, C₆-C₁₂ heteroaryloxy, C₆-C₁₂ fused aryloxy, C₆-C₁₂ fused heterocyclo-oxy, C₆-C₁₂ aryloxycarbonyl, C₂-C₁₂ heterocyclo oxycarbonyl, C₂-C₁₂ heteroaryl, C₁-C₁₂ alkylamino, C₂-C₁₂ heterocycloamino, C₆-C₁₂ arylamino, C₁-C₁₂ alkylaminocarbonyl, C₁-C₁₂ alkylcarbonylamino, C₁-C₁₂ alkylsulfonamido, C₂-C₁₂ heterocyclosulfonamido, C₆-C₁₂ arylsulfonamido, C₁-C₁₂ alkylaminosulfonamido; or Rb and Rc could be linked to form C₂-C₁₂ cycloalkyl, C₂-C₁₂ cycloalkenyl, or C₁-C₁₂ cycloethereal group.

In another preferred embodiment of the invention:

the dashed line “

” is single bond;

-   -   the D and/or D¹ is each O, N(Ra), CH₂, CH(OH) or C(Rb)(Rc),         wherein

Ra is H, hydroxy, C₁-C₅ alkoxycarbonyl, C₃-C₆ cycloalkyloxycarbonyl, C₃-C₁₀cycloalkylaminocarbonyl, C₁-C₄ alkylaminosulfonamido, or C₂-C₁₀ heterocycloaminosulfonyl group; and the Rb and Rc could be linked to

form C₂-C₅ cycloalkyl, or C₁-C₂ cycloethereal group.

In another preferred embodiment of the invention, the Ar, Ar¹, Ar² and Ar³ are each, independently, selected from the group consisting of C₆-C₁₂ aryl, C₂-C₁₂ heteroaryl, C₈-C₁₂ fused aryl, and C₄-C₁₂ fused heteroaryl,

or Ar and Ar¹ or Ar¹ and Ar² may be linked each other to form C₁₀-C₁₂ fused alkylaryl or C₈-C₁₂ aryl group,

or Ar¹ or Ar² does not exist and the groups bonded to Ar¹ or Ar² are directly linked.

In another preferred embodiment of the invention, the Ar and Ar¹ are each selected from

or the Ar and Ar¹ are linked each other as a fused aryl or heteroaryl group represented by the structure

and the Ar² and Ar³ are

respectively.

In another preferred embodiment of the invention, E is N, and G is CH.

In another preferred embodiment of the invention, K is C₂-C₁₂ mono-heteroaryl, C₂-C₁₂ poly-heteroaryl, or C₂-C₁₂ fused-heteroaryl group.

In another preferred embodiment of the invention, K is represented by one of the following structures:

In another preferred embodiment of the invention, L and/or L¹ is selected from the group consisting of O, NH, or the L and/or L¹ does not exist.

In another preferred embodiment of the invention, Q and/or Q¹ are each, independently, selected from the group consisting of C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, C₁-C₁₂ alkylamino, C₃-C₁₂ cycloalkylamino, C₆-C₁₂ aryl, C₃-C₁₂ heteroaryl, C₃-C₁₂ poly-heteroaryl, C₃-C₁₂ fused aryl, and C₃-C₁₂ heteroaryl group, wherein when the L and/or L¹ does not exist, the Q and/or Q¹ does not exist.

In another preferred embodiment of the invention, Q and/or Q¹ is independently represented by one the following structures:

In another preferred embodiment of the invention, W and W¹ are each, independently, selected from the group consisting of carbonyl, thiocarbonyl, C₁-C₁₂ alkyl, C₆-C₁₂ aryl, and C₂-C₁₂ heteroaryl group.

In another preferred embodiment of the invention, W and W¹ are each a carbonyl group.

In another preferred embodiment of the invention, W² and W³ are each, independently, selected from the group consisting of a carbonyl, thiocarbonyl, sulfonyl, C₁-C₁₂ alkyl, C₂-C₁₂ heterocyclo, C₆-C₁₂ aryl, and C₂-C₁₂ heteroaryl group.

In another preferred embodiment of the invention, W² and W³ are each a carbonyl group.

In another preferred embodiment of the invention, Y and Y¹ are each, independently, selected from the group consisting of H, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₆-C₁₂ aryl, C₁-C₁₂ alkylcarbonyl, C₆-C₁₂ arylcarbonyl, C₂-C₁₂ heterocyclocarbonyl, C₁-C₁₂ alkoxycarbonyl, C₁-C₁₂ cycloalkyl-oxy-carbonyl, C₆-C₁₂ aryloxycarbonyl, C₂-C₁₂ heteroaryloxycarbonyl, C₁-C₁₂ alkylaminocarbonyl, C₁-C₁₂ alkylsulfonyl, C₃-C₁₂ cycloalkylsulfonyl, C₆-C₁₂ arylsulfonyl, C₁-C₁₂ alkylamino sulfonyl, C₃-C₁₂ cycloalkylaminosulfonyl, and C₆-C₁₂ arylaminosulfonyl group.

In another preferred embodiment of the invention, Y and Y¹ are a C₁-C₅ alkoxycarbonyl, or C₁-C₅ alkylaminocarbonyl group.

In another preferred embodiment of the invention, Z and Z¹ are each, independently, selected from the group consisting of H, hydroxy, amino, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₁-C₁₂ alkoxy, C₃-C₁₂ cycloalkyl-oxy, C₁-C₁₂ alkylamino, C₃-C₁₂ cycloalkylamino, C₂-C₁₂ heterocyclo, C₂-C₁₂ heterocycloamino, C₆-C₁₂ aryl, C₆-C₁₂ aryloxy, C₆-C₁₂ arylamino, C₃-C₁₂ heteroaryloxy, C₃-C₁₂ heteroarylamino, C₁-C₁₂ alkylsulfonamido, C₃-C₁₂ cycloalkylsulfonamido, C₆-C₁₂ arylsulfonamido, C₁-C₁₂ alkoxysulfonamido, C₃-C₁₂ cycloalkyl-oxy-sulfonamido, C₆-C₁₂ aryloxysulfonamido, C₁-C₁₂ alkylaminosulfonamido, C₃-C₁₂ cycloalkylaminosulfonamido, and C₆-C₁₂ arylaminosulfonamido group.

In another preferred embodiment of the invention, Z and Z¹ are C₁-C₁₂ alkoxy, or C₁-C₁₂ alkylamino group

In another preferred embodiment of the invention, R¹, R², R³ and R⁴ are each, independently, selected from the group consisting of H, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₂-C₁₂ heterocyclo, C₆-C₁₂ aryl, C₂-C₁₂ heteroaryl, C₁-C₁₂ alkoxycarbonyl, C₆-C₁₂ aryloxycarbonyl, C₂-C₁₂ heterocyclo-oxy carbonyl, C₁-C₁₂ alkylaminocarbonyl, C₁-C₁₂ alkylaminosulfonamido, C₂-C₁₂ heterocycloamino sulfonyl, and C₆-C₁₂ arylaminosulfonyl group.

In another preferred embodiment of the invention, R¹ does not exist, R² is H, R³ is H, and R⁴ is H.

In another preferred embodiment of the invention, R⁵, R⁶, R⁷ and R⁸ are each, independently, selected from the group consisting of H, halogen, hydroxy, cyano, amino, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₂-C₁₂ heterocyclo, C₁-C₁₂ alkoxy, C₁-C₁₂ alkylamino, C₂-C₁₂ heterocycloamino, C₆-C₁₂ aryl, C₆-C₁₂ arylamino, C₁-C₁₂ alkoxycarbonylamino, C₁-C₁₂ alkylaminocarbonylamino, C₁-C₁₂ alkylsulfonamido, C₂-C₁₂ heterocyclosulfonamido, C₆-C₁₂ arylsulfonamido, and C₁-C₁₂ alkylaminosulfonamido,

or R⁵ and R⁶ are linked to form a cyclo group,

or R⁷ and R⁸ are linked to each other to form a cyclo group.

In another preferred embodiment of the invention:

R⁵ and R⁷ are H; and

R⁶ and R⁸ are a C₁-C₆ alkyl, C₂-C₆ heterocyclo, C₆-C₁₀ aryl, or C₃-C₈ heteroaryl group.

In another preferred embodiment of the invention, R⁹, R¹⁰, R¹¹ and R¹² are each, independently, selected from the group consisting of H, halogen, hydroxy, cyano, amino, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₁-C₁₂ alkoxy, C₁-C₁₂ alkylamino, C₂-C₁₂ heterocycloamino, C₆-C₁₂ aryl, C₃-C₁₂ heteroaryl, C₆-C₂₀ arylamino, and C₁-C₁₂ alkoxycarbonylamino,

or R⁹ and R¹⁰ may be linked to each to form a cyclo or spiro group, and

R¹¹ and R¹² may be linked to each other to form a cyclo or spiro group.

In another preferred embodiment of the invention, R⁹, R¹⁰, R¹¹ and R¹² are H.

In the second aspect, the present invention provides a pharmaceutical composition comprising one or more compounds selected from the structure Ia or Ib.

The third aspect of the present invention provides a pharmaceutical combination of any one or more compounds of the structure Ia or Ib in a therapeutically effective dose and/with a second or a third medicament in a therapeutically effective dose. Thus, the present invention provides a pharmaceutical composition, comprising at least one compound described above in a therapeutically effective dose and at least one additional medicament in a therapeutically effective dose.

The fourth aspect of the present invention provides a pharmaceutical combination of any compound of the structure Ia or Ib with any HIV inhibitors including but not limited to Indinavir or Ritonavir. Thus, the present invention provides a pharmaceutical composition, comprising at least one compound described above in a therapeutically effective dose and at least one HIV inhibitor in a therapeutically effective dose.

The fifth aspect of the present invention provides a pharmaceutical combination of at least one compound described above and any hepatitis B virus (HBV) inhibitor including but not limited to Lamivudine, Telbivudine, Adefovir, Entecavir, Tenofovir, or Clevudine.

The sixth aspect of the present invention provides a method for inhibiting HCV by using one or more compounds of the structure Ia or Ib in a therapeutically effective dose and a second or a third medicament in a therapeutically effective dose. Thus, the present invention provides a method of inhibiting HCV, comprising administering an effect amount of a compound or composition described above to a subject in need thereof.

The seventh aspect of the present invention provides a method for inhibiting HCV by using one or more compounds of the structure Ia or Ib and in combination with any or combined one or more of (1) Immune modulators including but not limited to Interferons, pegulated-interferons, or interferon derivatives, (2) HCV protease inhibitors, (3) HCV polymerase inhibitors, (4) nucleosides and its derivatives, (5) Cyclophilin inhibitors, (6) Glucosidase I inhibitors, (7) IMPDH inhibitors, (8) Caspase inhibitors, (9) TLR agonists, (10) HIV inhibitors, (11) anti-inflammatory drugs, (12) Cancer drugs, or (13) other compounds not covered from above (1)-(12).

Overall, all prepared new polyaryl and polyheteroaryl based antiviral compounds have been evaluated for their potency and toxicity. The present invention explores the relationship between the structures of new polyaryl and polyheteroaryl compounds and potency of HCV inhibition, and finally to provide valuable clue and potential effective and safe HCV inhibitors.

The present invention not only relates to design and synthesize the novel antiviral compounds as HCV-NS5A inhibitors, but also explores the relation between different novel polyaryl and fused heteroaryl compounds and their activity of HCV-NS5A inhibition, and finally to optimize and develop one of the best-in-class HCV-NS5A inhibitors.

Thus, the present invention also provides pharmaceutical composition comprising the compound described above and a pharmaceutically acceptable carrier.

The present invention also provides a composition comprising at least one compound as described above and at least one compound selected from the group consisting of an HIV inhibitor and a hepatitis B virus (HBV) inhibitor.

The present invention also provides a composition comprising at least one compound as described above and at least one compound selected from the group consisting of Lamivudine, Telbivudine, Adefovir. Entecavir, Tenofovir and Clevudine.

The present invention also provides a composition comprising at least one compound as described above and at least one compound selected from the group consisting of (1) Immune modulators, (2) HCV protease inhibitors, (3) HCV polymerase inhibitors, (4) nucleosides and derivatives thereof, (5) Cyclophilin inhibitors, (6) Glucosidase I inhibitors, (7) IMPDH inhibitors, (8) Caspase inhibitors, (9) TLR agonists, (10) HIV inhibitors, (11) anti-inflammatory drugs, and (12) anti-cancer drugs.

The present invention also provides a method of inhibiting Hepatitis C virus comprising contacting Hepatitis C virus with an effective amount of the compound as described above.

The present invention also provides a method of treating a subject infected with Hepatitis C virus comprising administering an effective amount of the compound as described above to the subject.

The present invention also provides a method of treating a subject infected with Hepatitis C virus comprising administering an effective amount of the composition as described above to the subject.

The present invention also provides a method of treating a subject infected with Hepatitis C virus comprising administering an effective amount of the composition as described above to the subject.

The present invention also provides a method of treating a subject infected with Hepatitis C virus comprising administering an effective amount of the composition as described above to the subject.

The present invention also provides a method of treating a subject infected with Hepatitis C virus comprising administering an effective amount of the composition described above to the subject.

DETAILED DESCRIPTION OF THE INVENTION

Details of the present invention are set forth in the following description for preparation and biological activity study of new HCV inhibitors Ia-Ib. The advantages of the present invention will be significantly observed from the following detailed description.

As used herein, the term “alkyl” refers to any linear or branched chain alkyl group having a number of carbon atoms and/or “alkylene” in the specified range, wherein one or more hydrogens could be replaced by one or more halogens.

The term “alkoxy” refers to an “alkyl-O—” group.

The term “cycloalkyl” refers to any cyclic ring of an alkane or alkene having a number of carbon atoms and/or “alkylene” in the specified range, wherein one or more hydrogens could be replaced by one or more halogens.

The term “cycloalkyl-oxy” refers to a “cycloalkyl-O—”.

The term “cycloalkyl-amino” refers to a “cycloalkyl-N(Ra)-”.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine and iodine atoms (or referred as fluoro, chloro, bromo, and iodo).

The term “carbonyl” refers to a “—C(O)—” group.

The term “alkylcarbonyl” refers to an “alkyl-C(O)—” group.

The term “alkoxy carbonyl” refers to an “alkyl-O—C(O)—” group.

The term “alkylamino carbonyl” refers to an “alkyl-NH—C(O)—” or “dialkyl-N—C(O)—” group.

The term “sulfonamido” refers to a “—S(O)₂NH—” or “—S(O)₂N(Ra)-” group, wherein Ra is alkyl or alkylcarbonyl group.

The term “alkyl sulfonamido” refers to an “alkyl-S(O)₂NH—” or “alkyl-S(O)₂N(Ra)-” group, wherein Ra is alkyl or alkylcarbonyl group.

The term “alkoxy sulfonamido” refers to an “alkyl-O—S(O)₂NH—” or “alkyl-O—S(O)₂N(Ra)-” group, wherein Ra is alkyl or alkylcarbonyl group.

The term “heteroaryl” refers to an aryl group with 1-3 hetero atoms including O, N, and/or S atoms.

The term “fused heteroaryl” refers to a bi-cyclic, tri-cyclic or tetra-cyclic heteroaryl group with 1-5 hetero atoms such as O, N, and/or S atoms.

The term “poly-heteroaryl” refers to a bi-, tri- or tetra-heteroaryl functional group with 1-5 hetero atoms (e.g., O, N, S, and P) in one or more fused rings.

The term “poly-heterocyclic” refers to a bi-cyclic, tri-cyclic or tetra-cyclic functional group with 1-5 hetero atoms (e.g., O, N, S, and P) in one or more fused rings.

The term “composition” is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.

The term “pharmaceutically acceptable” means that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.

The term “effective amount” means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The term also includes herein the amount of active compound sufficient to inhibit HCV NS3 protease and thereby elicit the response being sought (i.e., an “inhibition effective amount”). When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound.

The present invention provides two classes of novel antiviral compounds Ia-Ib, and pharmaceutically acceptable salts, and/or hydrates as HCV NS5A inhibitors with high potency. Moreover, toxicity study is determined to be non-toxic (LD₅₀>10,000) for most of highly potent HCV-NS5A inhibitors.

Synthesis of New Antiviral Compounds with General Structure Ia-Ib:

The reagents and raw materials used in the present invention are all commercially available.

Abbreviations of chemical materials, reagents, and solvents related to the synthesis of antiviral compounds in the present invention are listed in the parts of exemples.

The compounds in the present invention could be synthesized by normal raw materials through several synthetic methods after designing the structure of different compounds in the present invention.

The present disclosure relates to the following key innovations:

First, compounds SM1 and SM2 with heterocyclic functional groups in structural figures 1 and 2 were subjected to the amidation coupling reaction to offer the intermediate 3 (IIa). Subsequently, the protecting groups (i.e., PG or/and PG 1) in compound 3 were cleaved to offer the intermediate 4 or 5, respectively, followed by the coupling or amidation reaction to afford the novel compound 6 of formula Ia (see structural FIG. 3). The preparation method of these compounds were shown in the following schemes 1-3, respectively: wherein, the “X” group of SM1 and SM3 were selected from bromine (Br), and “Y” group of the SM2 and SM4 was selected from boric acid or boric acid ester in schemes 1 and 2.

The present invention also provides the preparation methods (1-3) of the compounds shown in Ia and Ib, as well as their stereoisomers, tautomers, esterification or amidation prodrugs and the pharmaceutically acceptable salts. These methods were described in the following sections:

Method 1:

Method 2:

The Compound 6 (Ia) was also obtained by the coupling reaction of the compound SM3 with another compound SM4, respectively:

Method 3:

Another class of compounds 6fa-6fy (Ib) was also obtained by the coupling reaction of the compounds SM3 with other compounds SM4, respectively:

In the following example, the compounds SM3 (SM-3a to SM-3di) in structural FIG. 1 and heterocyclic compounds SM4 (SM-4a to SM-4bk) in structural FIG. 2 were subjected to the catalytic coupling reactions (Scheme 1) by Pd-based catalyst to prepare a series of novel compounds 6 of the formulas Ia and Ib (6a-6ep and 6fa-6fy in structural FIG. 3).

Scheme 1:

Starting materials SM3 and SM4 in structural FIGS. 1 and 2 are critical materials required for the synthesis of target compounds Ia and Ib in present disclosure, the structures of them were shown as follows:

Structural FIG. 1: Chemical Materials SM3 (SM-3a to SM-3cs)

No. Structure of Raw Materials SM3  1

  SM-3a  2

  SM-3b  3

  SM-3c  4

  SM-3d  5

  SM-3e  6

  SM-3f  7

  SM-3g  8

  SM-3h  9

  SM-3i 10

  SM-3j 11

  SM-3k 12

  SM-3m 13

  SM-3n 14

  SM-3p 15

  SM-3q 16

  SM-3r 17

  SM-3s 18

  SM-3t 19

  SM-3u 20

  SM-3v 21

  SM-3w 22

  SM-3x 23

  SM-3y 24

  SM-3z 25

  SM-3aa 26

  SM-3ab 27

  SM-3ac 28

  SM-3ad 29

  SM-3ae 30

  SM-3af 31

  SM-3ag 32

  SM-3ah 33

  SM-3ai 34

  SM-3aj 35

  SM-3ak 36

  SM-3am 37

  SM-3an 38

  SM-3ap 39

  SM-3aq 40

  SM-3ar 41

  SM-3as 42

  SM-3at 43

  SM-3au 44

  SM-3av 45

  SM-3aw 46

  SM-3ax 47

  SM-3ay 48

  SM-3az 49

  SM-3ba 50

  SM-3bb 51

  SM-3bc 52

  SM-3bd 53

  SM-3be 54

  SM-3bf 55

  SM-3bg 56

  SM-3bh 57

  SM-3bi 58

  SM-3bj 59

  SM-3bk 60

  SM-3bm 61

  SM-3bn 62

  SM-3bp 63

  SM-3bq 64

  SM-3br 65

  SM-3bs 66

  SM-3bt 67

  SM-3bu 68

  SM-3bv 69

  SM-3bw 70

  SM-3bx 71

  SM-3by 72

  SM-3bz 73

  SM-3ca 74

  SM-3cb 75

  SM-3cc 76

  SM-3cd 77

  SM-3ce 78

  SM-3cf 79

  SM-3cg 80

  SM-3ch 81

  SM-3ci 82

  SM-3cj 83

  SM-3ck 84

  SM-3cm 85

  SM-3cn 86

  SM-3cp 87

  SM-3cq 88

  SM-3cr 89

  SM-3cs

Chemical materials SM4-4a to SM-4bk) in structural fig. 2 are the critical compounds in present deisclosure, the structures of them were shown as follows:

Structural FIG. 2: Chemical Materials SM4 (SM-4a to SM-3bk)

No. Structure of Raw Materials SM4 1

  SM-4a 2

  SM-4b 3

  SM-4c 4

  SM-4d 5

  SM-4e 6

  SM-4f 7

  SM-4g 8

  SM-4h 9

  SM-4i 10

  SM-4j 11

  SM-4k 12

  SM-4m 13

  SM-4n 14

  SM-4p 15

  SM-4q 16

  SM-4r 17

  SM-4s 18

  SM-4t 19

  SM-4u 20

  SM-4v 21

  SM-4w 22

  SM-4x 23

  SM-4y 24

  SM-4z 25

  SM-4aa 26

  SM-4ab 27

  SM-4ac 28

  SM-4ad 29

  SM-4ae 30

  SM-4af 31

  SM-4ag 32

  SM-4ah 33

  SM-4ai 34

  SM-4aj 35

  SM-4ak 36

  SM-4am 37

  SM-4an 38

  SM-4ap 39

  SM-4aq 40

  SM-4ar 41

  SM-4as 42

  SM-4at 43

  SM-4au 44

  SM-4av 45

  SM-4aw 46

  SM-4ax 47

  SM-4ay 48

  SM-4az 49

  SM-4ba 50

  SM-4bb 51

  SM-4bc 52

  SM-4bd 53

  SM-4be 54

  SM-4bf 55

  SM-4bg 56

  SM-4bh 57

  SM-4bi 58

  SM-4bj 59

  SM-4bk

The designed antiviral compounds 6a-6ep (Ia) and 6fa-6fy (Ib) were synthesized and listed in structural FIG. 3 by the synthetic methods 1-3 described above.

Structural FIG. 3a: The Target Antiviral Compounds 6a-6ep

No. Prepared Compounds 6a-6ep of Formula Ia Ia-1

  6a Ia-2

  6b Ia-3

  6c Ia-4

  6d Ia-5

  6e Ia-6

  6f Ia-7

  6g Ia-8

  6h Ia-9

  6i Ia-10

  6j Ia-11

  6k Ia-12

  6m Ia-13

  6n Ia-14

  6p Ia-15

  6q Ia-16

  6r Ia-17

  6s Ia-18

  6t Ia-19

  6u Ia-20

  6v Ia-21

  6w Ia-22

  6x Ia-23

  6y Ia-24

  6z Ia-25

  6aa Ia-26

  6ab Ia-27

  6ac Ia-28

  6ad Ia-29

  6ae Ia-30

  6af Ia-31

  6ag Ia-32

  6ah Ia-33

  6ai Ia-34

  6aj Ia-35

  6ak Ia-36

  6am Ia-37

  6an Ia-38

  6ap Ia-39

  6aq Ia-40

  6ar Ia-41

  6as Ia-42

  6at Ia-43

  6au Ia-44

  6av Ia-45

  6aw Ia-46

  6ax Ia-47

  6ay Ia-48

  6az Ia-49

  6ba Ia-50

  6bb Ia-51

  6bc Ia-52

  6bd Ia-53

  6be Ia-54

  6bf Ia-55

  6bg Ia-56

  6bh Ia-57

  6bi Ia-58

  6bj Ia-59

  6bk Ia-60

  6bm Ia-61

  6bn Ia-62

  6bp Ia-63

  6bq Ia-64

  6br Ia-65

  6bs Ia-66

  6bt Ia-67

  6bu Ia-68

  6bv Ia-69

  6bw Ia-70

  6bx Ia-71

  6by Ia-72

  6bz Ia-73

  6ca Ia-74

  6cb Ia-75

  6cc Ia-76

  6cd Ia-77

  6ce Ia-78

  6cf Ia-79

  6cg Ia-80

  6ch Ia-81

  6ci Ia-82

  6cj Ia-83

  6ck Ia-84

  6cm Ia-85

  6cq Ia-86

  6cu Ia-87

  6cv Ia-88

  6cw Ia-89

  6cx Ia-90

  6cy Ia-91

  6cz Ia-92

  6da Ia-93

  6db Ia-94

  6dc Ia-95

  6dd Ia-96

  6de Ia-97

  6df Ia-98

  6dg Ia-99

  6dh Ia-100

  6di Ia-101

  6dj Ia-102

  6dk Ia-103

  6dm Ia-104

  6dn Ia-105

  6dp Ia-106

  6dq Ia-107

  6dr Ia-108

  6ds Ia-109

  6dt Ia-110

  6du Ia-111

  6dv Ia-112

  6dw Ia-113

  6dy Ia-114

  6dz Ia-115

  6ea Ia-116

  6eb Ia-117

  6ec Ia-118

  6ej Ia-119

  6ek Ia-120

  6em Ia-121

  6en Ia-122

  6ep

Structural FIG. 3b: The Target Antiviral Compounds 6Fa-6fy

No. Prepared Compounds 6fa-6fy of Formula Ib Ib-1

Ib-2

Ib-3

Ib-4

Ib-5

Ib-6

Ib-7

Ib-8

Ib-9

Ib-10

Ib-11

Ib-12

Ib-13

Ib-14

Ib-15

Ib-16

Ib-17

Ib-18

Ib-19

Ib-20

Ib-21

Ib-22

Ib-23

The present invention provides the application of compounds Ia-Ib described above, their stereoisomers, tautomers, esterification or amidation prodrugs and pharmaceutically acceptable salts for development of new drugs inhibiting HCV.

The present disclosure also provided the application of one or one more class of compounds Ia-Ib mixtures described above, their stereoisomers, tautomers, esterification or amidation prodrugs and pharmaceutically acceptable salts for development of new drugs inhibiting HCV.

The antiviral compounds (Ia-Ib) mentioned herein may contain a non-aromatic double bond and one or more asymmetric centers. Thus, they can occur as racemates and racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, tautomers, and cis- or trans-isomeric forms, and/or hydrates. All such isomeric forms are contemplated.

In this invention, some detailed embodiments were illustrated for the further explanation of the invention, but the effective range of the invention was not limited to the detailed embodiments described in present invention. The compounds in present invention could have bis-phenyl or fused bi-heteroaryl groups as well as one or one more heterocyclic chiral centers. Therefore, this kind of compounds could be racemic mixtures, pure diastereoisomers, tautomers. The prepared compounds 6a-6ep(Ia) and 6fa-6fy(Ib) in the invention are chiral heterocycles, in which the optical purity of natural and non-natural amino acids were determined by optical rotation or/and chiral column chromatography. The structural identification of each final compound (including 6a-6ep, 6fa-6fy, and the following reference compounds Ref-1 “BMS790052”, Ref-2 “GS-5885”, Ref-3 and Ref-4 “IDX719”, etc) was each selected to compare the potency and toxicity with the prepared compounds 6a-6ep(Ia) and 6fa-6fy(Ib), respectively.

So far, there is no any effective animal model for scientists to evaluate the efficacy of new compounds by inhibiting the HCV NS5A replicon. The compounds described above in the present invention can be preliminarily screened by evaluating the IC₅₀ and/or EC₅₀ results for their bioactivity and potency in treating HCV infection by an in vitro assay as follows, then have some highly potent HCV inhibitors selected for further PK and toxicity studies before clinic trial. Other methods will also be apparent for scientists in pharmaceuticals.

Antiviral Assay for Inhibition Activity (EC50):

The study is completed by a new constructed double reporter genes replicon assay system, the capacity of viral replicon in infected cell is determined by detecting the reporter gene Renilla luciferase. The relationship of reporter genes, HCV RNA replicon and viral proteins is well linear. 8 gradient concentrations for 2-fold dilution, 3 wells. 3 times repetition and 1 or 2 control drugs are set to finally determine EC50 of compound.

Acute Toxicity Study (MTD):

Materials and Methods for MTD Study are as follows:

Test Group:

Animals were fed freely for adaptation more than 1 week. Healthy rats, body weight between 170-190 g, were divided randomly into 3 groups, 5 male and 5 female in each group. Healthy mice, body weight between 18-22 g, were divided randomly into 22 groups, 5 male and 5 female in each group.

MTD Results:

Dozens of highly potent compounds (e.g., 6ba, 6bx, 6by, 6bz, 6fc, 6fd, 6fg, 6fi, 6fm, 6fp, etc.) were tested by MTD, and there were no any test-article related death and no any adverse events observed for each tested compound.

Administration Method:

In rats, the compound weighing 21.00 g, serial number 1-3 respectively, adding 0.7% sodium carboxymethyl cellulose solution 30.00 g, high-speed homogenizer machine 15000 RPM, 10 min mixing, the rats were fed once, oral dose 10000 mg/kg. In mice, the compound weighing 2.00 g, serial number 4-25 respectively, adding 0.7% sodium carboxymethyl cellulose solution 8.00 g, high-speed homogenizer machine 10000 RPM, 10 min mixing, the mice were fed once, oral dose 10000 mg/kg.

Clinical Observation:

Animals were observed every hour after administration in the first day, and behavior observation daily continuous for a week. Dead animals were necropsied, gross pathology of the organs were observed and recorded.

Evaluation of Toxicity:

Toxicity was evaluated by animal mortality, signs of clinical behavior and others.

Among all of synthesized compounds 6a-6ep and 6fa-6fy and another reference compound BMS790052, the results of HCV-NS5A inhibition test are listed in the following Table 1; where the scope of potent activity (EC₅₀): “A” refers to activity EC₅₀)≧50 nM, “B” refers to activity EC₅₀ of 1.0-49.9 nM, and “C” refers to activity EC₅₀ of 0.001-0.999 nM.

TABLE 1 Activity of Novel Antiviral Compounds Used as inhibiting HCV NS5A EC₅₀ For Compound GT-1a of NS5A No. No. Replicon 1 6a C 2 6b A 3 6c A 4 6d b 5 6e A 6 6f A 7 6g A 8 6h A 9 6i C 10 6j A 11 6k A 12 6m B 13 6n A 14 6p A 15 6q A 16 6r A 17 6s C 18 6t A 19 6u B 20 6v A 21 6w A 22 6x C 23 6y C 24 6z C 25 6aa C 26 6ab C 27 6ac C 28 6ad C 29 6ae C 30 6af C 31 6ag C 32 6ah C 33 6ai C 34 6aj C 35 6ak C 36 6am C 37 6an C 38 6ap C 39 6aq C 40 6ar C 41 6as C 42 6at C 43 6au C 44 6av C 45 6aw C 46 6ax C 47 6ay C 48 6az C 49 6ba C 50 6bb A 51 6bc B 52 6bd C 53 6be C 54 6bf A 55 6bg A 56 6bh C 57 6bi C 58 6bj C 59 6hk C 60 6bm C 61 6bn C 62 6bp C 63 6bq C 64 6br C 65 6bs A 66 6bt C 67 6bu C 68 6bv A 69 6bw A 70 6bx C 71 6by C 72 6bz C 73 6ca C 74 6cb A 75 6cc A 76 6cd A 77 6ce C 78 6cf C 79 6cg C 80 6ch C 81 6ci C 82 6cj C 83 6ck C 84 6cm C 85 6cq B 86 6cu C 87 6cv C 88 6cw C 89 6cx C 90 6cy C 91 6cz C 92 6da C 93 Gdb C 94 6dc C 95 6dd C 96 6de C 97 6df C 98 6dg C 99 6dh C 100 6di C 101 6dj B 102 6dk C 103 6dm C 104 6dn C 105 6dp C 106 6dq C 107 6dr C 108 6ds C 109 6dt C 110 6du C 111 6dv C 112 6dw C 113 6dx C 114 6dy C 115 6dz C 116 6ca C 117 6cb C 118 6cc C 119 6cj C 120 6ck B 121 6cm B 122 6cn B 123 6cp B 124 6fa C 125 6fb C 126 6fe C 127 6fd C 128 6fe C 129 6ff C 130 6fg C 131 6fh C 132 6fi C 133 6fj C 134 6fk C 135 6fm C 136 6fn C 137 6fp C 138 6fq C 139 6fr C 140 6fs C 141 6ft C 142 6fu C 143 6fv C 144 6fw C 145 6fx C 146 6fy C 147 Ref-1 C 148 Ref-2 C 149 Ref-3 C 150 Ref-4 C

TABLE 2 Antiviral Activity (EC₅₀) of Several Selected Anitviral Compounds Used as HCV NS5A Inhibitors with Excellent Potency and Safety Compound EC₅₀ for Replicon (pM) of GT-1a to GT-6a ID 1a 1b 2a 3a 4a 5a 6a 6ba 39 12 16 173 10 23 221 6dy 11 14 6 15 8 23 24 6fd 21 11 5 15 8 23 111 6fi 20 5 7 26 5 13 55 6fm 9 13 8 24 12 29 23 Ref-1 52 21 29 218 11 36 118 Ref-2 88 N/A N/A N/A N/A N/A N/A Ref-3 51 N/A N/A N/A N/A N/A N/A Note: N/A: Not Available in Table 2.

The activity screening results in Tables 1 and 2 show that: (1) many prepared compounds have excellent HCV inhibition activity (picomolar potency), (2) Several of fused-heteroaryl core based compounds 6fa-6fy (Ib) have picomolar pan-genotypic activity for all GT-1a to GT-6a, better than the referred compound BMS790052.

Overall, most of new prepared poly-aryl and fused-heteroaryl compounds in this invention have been evaluated with high potency to inhibit HCV. Moreover, the present invention explores the insight relationship between the structures of new antiviral compounds and potency of HCV NS5A inhibition, which provides valuable clue to develop an effective HCV inhibitor among the discovered novel compounds Ia-Ib. In summary, based on the detail experimental results in Table 2, there were several “Me-Better” and a “Best-in-Class” antiviral compounds discovered with excellent “potency, safety, PK and metabolic stability” in each class of novel optimized compounds Ia and Ib by incorporating new

functional groups, especially by incorporating

in Ia-Ib (wherein D=CH) instead of

group in comparison with other compounds in previously reported papers and patents, which appears very competitive and/or much better than other reference compounds (e.g., compared with “Ref-1 to Ref-4”, respectively) and provides several highly valuable lead compounds for further development of a highly competitive HCV NS5A inhibitor later.

In the following section were the detailed examples of the synthesis and biological activities of different kinds of compounds and their intermediates.

Instruments and Materials Related to Examples are as Follows:

Infrared (IR) spectra were recorded on Thermo Nicolet company Fourier Transform AVATAR™ 360 E.S.P™ spectrophotometer (Unit: cm⁻¹).

¹H-NMR spectra were recorded on a Varian Mercury Plus 400 or 500 (400 or 500 MHz) spectrometer, Chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CHCl₃: 7.26 ppm). Data are reported as follows: chemical shift, multiplicity (s: single, d: doublet, t: triplet, q: quartet, br: broad, m: multiplet) and coupling constants.

Unless otherwise noted, mass spectra were obtained at Finnigan LCQ Advantage of liquid chromatography-mass spectrometer analysis, all reactions were conducted in oven and flame-dried glassware with vacuum-line techniques under an inert atmosphere of dry Ar. Solid metal organic compounds were stored in Ar in a drying box.

THF was distilled from sodium metal and benzophenone. DCM, pentane and hexane were distilled form calcium hydride. Special raw material and intermediate in the invention were ordered by contract synthesis from Zannan SciTech Co., Let in China, others reagents were purchased from Shanghai reagent company, Aldrich, Acros etc. As intermediates or products during the synthesis is not required for the reaction and other tests the next step, the synthesis is repeated until a sufficient number of times. The invention of the prepared compounds of HCV protease (HCV NS5A) inhibitory activity test was performed by CRO service units such as WuXi AppTec etc.

Abbreviations of chemical materials, reagnets, and solvents related to the present invention are listed as follows:

AIBN: azobisisobutyronitrile

Boc: tert-butoxycarbonyl

(Boc)₂O: di-tert-butyl carbonate

CDI: N,N′-carbonyldiimidazole imidazole

DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene

HATU: 2-(7-benzotriazole azo)-N,N,N′,N′-tetramethyl urea phosphate hexafluoride

NBS: N-bromosuccinimide

DMAP: 4-dimethylaminopyridine

DIEA: N,N-diisopropyl ethylamine

Pd/C: Palladium carbon

HMTA: hexamethylene tetramine

HOAc: acetic acid

TFA: trifluoroacetic acid

TsOH: p-toluenesulfonate

ACN: acetonitrile

DCM: dichloromethane

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

Et₂O: diethyl ether

EA: ethyl acetate

PE: petroleum ether

THF: tetrahydrofuran

TBME: tert-butyl methyl ether

EXAMPLE 1 Synthesis of Compound 6a

The starting materials SM-3a (0.10 g, 0.2 mmol) and SM-4i (0.15 g, 0.2 mmol, 1.0 eq.) were dissolved in 5 mL DMF in a 25 mL 3-neck flask, then the potassium carbonate (0.6 mmol, 3.0 eq.) and water (3 mL) were added with stirring. Under argon protection, the reaction mixture was heated to 100° C., then tetrakis (triphenylphosphine) palladium (0.01 g) was added in one portion. The mixture was stirred at 100° C. until HPLC showed that the reaction was completed. The reaction mixture was filtered, then water was added and extracted with ethyl acetate, combined the organic phase, washed with brine, purified by column chromatography to obtain a yellow solid 6a (61 mg, yield: 31%).

¹H NMR for the product 6a (300 MHz, CDCl₃): δ 7.49-7.84 (m, 8H), 7.22-7.24 (m, 2H), 6.65-6.78 (m, 2H), 5.98-5.99 (m, 2H), 5.51-5.55 (m, 2H), 5.43-5.51 (m, 2H), 5.27-5.31 (m, 1H), 4.60-4.72 (m, 4H), 4.12-4.38 (m, 3H), 3.85-3.91 (m, 1H), 3.64-3.74 (m, 4H), 3.49 (s, 3H), 2.54-2.61 (m, 1H), 2.36-2.42 (m, 1H), 1.91-2.28 (m, 5H), 0.85-0.91 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6a: nm/z calculated 944.4. founded 944.5.

EXAMPLE 2 Synthesis of Compound 6b

Compound 6b was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3c (0.24 mmol) and SM-4j (0.24 mmol) instead of SM-3a and SM-4i, a yellow solid product 6b (62 mg, yield: 25%) was obtained.

¹H NMR for the product 6b (500 MHz, CDCl₃): δ 7.48-7.84 (m, 8H), 6.66-6.77 (m, 2H), 5.98 (m, 2H), 5.14-5.57 (m, 5H), 4.60-4.72 (m, 4H), 4.13-4.32 (m, 3H), 3.84 (m, 2H), 3.71 (m, 1H), 3.37 (m, 1H), 2.58 (m, 1H), 1.93-2.36 (m, 8H), 1.25-1.45 (m, 20H), 0.87-1.13 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6b: m/z calculated 1028.5. founded 1028.6.

EXAMPLE 3 Synthesis of Compound 6c

Compound 6c was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3e (0.24 mmol) and SM-4k (0.24 mmol) instead of SM-3a and SM-4i, a yellow solid 6c (78 mg, yield: 31%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6c: nm/z calculated 1056.6. founded 1056.7.

EXAMPLE 4 Synthesis of Compound 6d

Compound 6d was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3a (0.29 mmol) and SM-4j (0.29 mmol) instead of SM-3a and SM-4i, a yellow solid 6d (160 mg, yield: 57%) was obtained.

¹H NMR for the product 6d (300 MHz, CDCl₃): δ 7.31-7.79 (m, 8H), 7.22-7.27 (m, 2H). 6.66-6.78 (m, 2H), 5.98-5.99 (m, 2H), 5.28-5.56 (m, 4H), 4.62-4.69 (m, 4H), 4.20-4.59 (m, 3H), 3.88-3.97 (m, 1H), 3.62-3.75 (m, 4H), 1.78-2.01 (m, 8H), 1.36-1.46 (m, 9H), 0.89-0.94 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6d: m/z calculated 986.5. founded 986.6.

EXAMPLE 5 Synthesis of Compound 6e

Compound 6e was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3i (0.14 mmol) and SM-4j (0.14 mmol) instead of SM-3a and SM-4i, a yellow solid 6e (48 mg, yield: 30%) was obtained.

¹H NMR for the product 6e (500 MHz, CDCl₃): δ 7.82 (brs, 2H), 7.50-7.61 (m, 6H), 6.66-6.78 (m, 4H), 5.98 (s, 2H), 5.97 (s, 2H), 5.55 (brs, 2H), 5.39-5.46 (m, 4H), 4.60-4.74 (m, 8H), 4.21-4.25 (m, 4H), 3.84-3.85 (m, 2H), 3.49 (s, 6H), 2.57 (m, 2H), 1.93-1.94 (m, 2H), 1.73 (m, 4H), 1.32 (m, 1H), 1.12 (m, 1H), 0.82-0.88 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6e: m/z calculated 1149.5. founded 1149.6.

EXAMPLE 6 Synthesis of Compound 6f

Compound 6f was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3j (0.2 mmol) and SM-4j (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6f (110 mg, yield: 42%) was obtained

¹H NMR for the product 6f (500 MHz, CDCl₃): δ 7.62-7.83 (m, 8H), 6.68-6.78 (m, 4H). 5.96-5.98 (m, 4H), 5.55 (s, 2H), 5.47 (s, 2H), 5.15 (m, 2H), 4.61-4.72 (m, 8H), 4.12-4.22 (m, 4H), 3.85 (m, 2H), 3.49 (s, 6H), 2.58 (m, 2H), 1.74-1.92 (m, 4H), 1.25-1.35 (m, 20H). 1.12 (m, 2H), 0.84 (s, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6f: m/z calculated 1233.6. founded 1233.6.

EXAMPLE 7 Synthesis of Compound 6g

Compound 6g was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3m (0.1 mmol) and SM-4m (0.1 mmol) instead of SM-3a and SM-4i, a yellow solid 6g (18 mg, yield: 17%) was obtained.

¹H NMR for the product 6g (400 MHz, CD₃OD): δ 7.38-7.34 (m, 1H), 7.00-6.96 (m, 2H), 6.11-6.03 (m, 1H), 5.43-5.39 (m, 1H), 5.29-5.27 (m, 1H), 4.65-4.64 (m, 2H), 4.62 (s, 2H), 4.57 (s, 2H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6g: m/z calculated 1257.6. founded 1257.6.

EXAMPLE 8 Synthesis of Compound 6h

Compound 6h was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3g (0.1 mmol) and SM-4m (0.1 mmol) instead of SM-3a and SM-4i, a yellow solid 6h (21 mg, yield: 20%) was obtained.

¹H NMR for the product 6h (400 MHz, CD₃OD): δ 7.38-7.34 (m, 1H), 7.00-6.96 (m, 2H), 6.11-6.03 (m, 1H), 5.43-5.39 (m, 1H), 5.29-5.27 (m, 1H), 4.65-4.64 (m, 2H), 4.62 (s, 2H), 4.57 (s, 2H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6h: m/z calculated 1052.5. founded 1052.6.

EXAMPLE 9 Synthesis of Compound 6i

Compound 6i was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3a (0.2 mmol) and SM-4n (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6i (105 mg, yield: 55%) was obtained.

¹H NMR for the product 6i (500 MHz, CDCl₃): δ 7.62-7.83 (m, 8H), 6.72 (s, 1H), 6.66 (s. 1H), 5.97 (s, 2H), 5.44-5.54 (m, 4H), 5.28 (m, 1H), 4.57-4.69 (m, 4H), 4.34 (m, 1H), 4.25 (m, 1H), 4.17 (m, 1H), 3.83-3.86 (m, 2H), 3.74-3.76 (m, 1H). 3.70 (s, 3H), 3.65 (m, 1H), 3.50 (s, 3H), 2.57 (m, 1H), 2.36 (m, 1H), 2.20 (m, 1H), 2.09-2.10 (m, 1H), 1.79-1.98 (m, 5H), 1.04-1.16 (m, 2H), 0.84-0.89 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6i: m/z calculated 944.4. founded 944.5.

EXAMPLE 10 Synthesis of Compound 6j

Compound 6j was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3c (0.2 mmol) and SM-4p (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6j (45 mg, yield: 20%) was obtained.

¹H NMR for the product 6j (500 MHz, CDCl₃): δ 7.83 (m, 2H), 7.51-7.64 (m, 6H), 6.72 (s, 1H), 6.64 (s, 1H), 5.97 (m, 2H), 5.14-5.56 (m, 5H), 4.55-4.67 (m, 4H), 4.13-4.31 (m, 3H), 3.82 (m, 2H), 3.48-3.60 (m, 2H), 2.57 (m, 1H), 2.32 (m, 1H), 1.72-2.07 (m, 7H), 1.08-1.32 (m, 20H), 0.84-0.90 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6j: m/z calculated 1028.5. founded 1028.6.

EXAMPLE 11 Synthesis of Compound 6k

Compound 6k was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3e (0.2 mmol) and SM-4q (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6k (45 mg, yield: 20%) was obtained.

¹H NMR for the product 6k (500 MHz, CDCl₃): δ 7.62-7.81 (m, 8H), 6.71 (s, 1H), 6.62 (s, 1H), 5.97 (s, 2H), 5.16-5.50 (m, 5H), 4.58-4.66 (m, 4H), 4.28-4.35 (m, 2H), 4.21-4.23 (d, J=9.5 Hz, 1H). 3.90 (m, 1H), 3.78 (m, 1H), 3.66 (m, 1H), 3.42 (m, 1H), 2.58 (m, 1H), 2.34 (m. 1H), 2.01-2.09 (m, 2H), 1.49-1.64 (m, 5H), 1.32 (s, 9H), 1.26 (s, 9H), 0.82-0.93 (m, 18H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6k: m/z calculated 1056.6. founded 1056.7.

EXAMPLE 12 Synthesis of Compound 6m

Compound 6m was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3a (0.2 mmol) and SM-4p (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6m (155 mg, yield: 79%) was obtained.

¹H NMR for the product 6m (500 MHz, CDCl₃): δ 7.58-7.82 (m, 8H), 6.71 (s, 1H), 6.64 (s, 1H), 5.97 (s, 2H), 5.46-5.55 (m, 3H), 5.18-5.28 (m, 2H), 4.56-4.66 (m, 4H), 4.35 (m, 1H), 4.15-4.24 (m, 2H), 3.84-3.89 (m, 2H), 3.67-3.75 (m, 5H), 2.58 (m, 1H), 2.37 (m, 1H). 2.22 (m, 1H), 2.10 (m, 1H), 1.91-2.05 (m, 3H), 1.36 (s, 9H), 1.07-1.13 (m, 4H), 0.84-0.90 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6m: m/z calculated 986.5. founded 986.6.

EXAMPLE 13 Synthesis of Compound 6n

Compound 6n was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3n (0.2 mmol) and SM-4n (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6n (54 mg, yield: 19%) was obtained.

¹H NMR for the product 6n (500 MHz, CDCl₃): δ 7.83 (brs, 2H), 7.50-7.63 (m, 6H), 6.72 (s, 2H), 6.66 (s, 2H), 5.97 (s, 4H), 5.36-5.54 (m, 6H), 4.57-4.68 (m, 8H), 4.24-4.27 (m, 2H), 4.16-4.19 (m, 2H), 3.84-3.85 (m, 2H), 3.51 (s, 6H), 2.55-2.59 (m, 2H), 1.92-1.94 (m, 2H), 1.66-1.68 (m, 4H), 1.32 (m, 1H), 1.12 (m, 1H), 0.84-0.88 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6n: m/z calculated 1149.6. founded 1149.6.

EXAMPLE 14 Synthesis of Compound 6p

Compound 6p was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3p (0.2 mmol) and SM-4p (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6p (124 mg, yield: 50%) was obtained.

¹H NMR for the product 6p (500 MHz, CDCl₃): δ 7.83 (brs, 2H), 7.51-7.63 (m, 6H), 6.71 (s, 2H), 6.64 (s, 2H). 5.97 (s, 4H), 5.48-5.54 (m, 4H). 5.17 (m, 2H), 4.55-4.66 (m, 8H), 4.14-4.22 (m, 4H), 3.59-3.84 (m, 2H), 2.58 (m, 2H), 1.69-2.05 (m, 6H), 1.26-1.36 (m, 20H), 0.84-0.90 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6p: m/z calculated 1233.6. founded 1233.6.

EXAMPLE 15 Synthesis of Compound 6q

Compound 6q was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3r (0.2 mmol) and SM-4r (0.2 mmol) instead of SM-3a and SM4i, a yellow solid 6q (46 mg, yield: 21%) was obtained.

¹H NMR for the product 6q (500 MHz, CDCl₃): δ 7.83-7.84 (m, 2H), 7.52-7.63 (m, 6H), 6.72 (s. 2H), 6.65 (s, 2H), 5.97 (s, 4H), 5.43-5.53 (m, 4H), 5.21 (m, 2H), 4.57-4.77 (m, 8H). 4.29 (m, 4H), 3.80-3.82 (m, 2H), 3.49 (m, 2H), 2.57 (m, 2H), 1.88-1.91 (m, 2H), 1.59-1.70 (m, 16H). 1.12-1.33 (m, 6H), 0.81-0.85 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6q: m/z calculated 1257.6. founded 1257.7.

EXAMPLE 16 Synthesis of Compound 6r

Compound 6r was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3g (0.1 mmol) and SM-4r (0.1 mmol) instead of SM-3a and SM-4i, a yellow solid 6r (49 mg, yield: 47%) was obtained.

¹H NMR for the product 6r (500 MHz, CDCl₃): δ 7.85-7.84 (m, 2H), 7.60 (m, 6H), 6.72 (s, 1H), 6.66 (s, 1H), 5.97 (s, 2H), 5.54 (m, 2H), 5.10-5.31 (m, 5H), 4.57-4.78 (m, 4H), 4.22-4.34 (m, 3H), 3.86 (m, 2H), 3.68 (m, 1H), 3.15-3.46 (m, 1H), 2.58 (m, 1H), 2.36 (m, 1H), 2.22-2.24 (m, 2H), 1.99-2.11 (m, 5H), 1.15-1.50 (m, 18H), 0.74-0.90 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6r: m/z calculated 1052.5. founded 1052.6.

EXAMPLE 17 Synthesis of Compound 6s

Compound 6s was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3a (0.2 mmol) and SM-4s (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6s (55 mg, yield: 31%) was obtained.

¹H NMR for the product 6s (500 MHz, CDCl₃): δ 7.57-7.67 (m, 4H), 7.21-7.25 (m, 2H). 6.93-7.07 (m, 3H), 5.55-5.57 (m, 2H), 5.46-5.47 (m, 2H), 5.24-5.27 (m, 1H), 4.69-4.84 (m, 4H), 4.32-4.36 (m, 1H), 4.22 (m, 1H), 4.10-4.14 (m, 1H), 3.84-3.86 (m, 1H), 3.68-3.73 (m, 6H), 3.43-3.46 (m, 3H), 2.94-2.95 (m, 1H), 2.56-2.58 (m, 1H), 2.33-2.35 (m, 1H), 2.20-2.22 (m, 1H), 2.08-2.11 (m, 1H), 1.92-2.02 (m, 3H), 0.84-0.89 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6s: m/z calculated 918.4. founded 918.5.

EXAMPLE 18 Synthesis of Compound 6t

Compound 6t was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3c (0.2 mmol) and SM-4t (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6t (132 mg, yield: 65%) was obtained.

¹H NMR for the product 6t (500 MHz, CDCl₃): δ 7.72-7.82 (m, 2H), 7.59 (s, 4H), 6.95-7.07 (m, 3H), 5.48-5.55 (m, 3H), 5.13-5.30 (m, 4H), 4.71-4.81 (m, 4H), 4.20-4.32 (m, 4H), 3.84-3.47 (m, 5H), 2.59-2.59 (m, 1H), 1.89-2.34 (m, 5H), 1.26 (s, 18H), 0.85-0.88 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6t: m/z calculated 1002.5. founded 1002.6.

EXAMPLE 19 Synthesis of Compound 6u

Compound 6u was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3a (0.2 mmol) and SM-4t (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6u (64 mg, yield: 35%) was obtained.

¹H NMR for the product 6u (500 MHz, CDCl₃): δ 7.58 (s, 4H), 7.21-7.23 (m, 1H), 6.95-7.06 (m, 3H), 6.80-6.82 (m, 1H), 5.46-5.53 (m, 3H), 5.23-5.30 (m, 3H), 4.71-4.80 (m, 3H), 4.32-4.33 (m, 1H), 4.19-4.20 (m, 1H), 3.82-3.85 (m, 1H), 3.65-3.74 (m, 4H), 2.94-2.96 (m, 1H), 2.88-2.89 (m, 1H), 2.62 (s, 4H), 2.33-2.34 (m, 1H), 2.18-2.22 (m, 2H), 1.89-2.10 (m, 4H). 1.25-1.31 (m, 9H), 0.83-0.8 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6u: m/z calculated 960.5. founded 960.6.

EXAMPLE 20 Synthesis of Compound 6v

Compound 6v was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3g (0.1 mmol) and SM-4u (0.1 mmol) instead of SM-3a and SM-4i, a yellow solid 6v (38 mg, yield: 37%) was obtained.

¹H NMR for the product 6v (500 MHz, CDCl₃): δ 7.77-7.82 (m, 3H), 7.54-7.62 (m, 5H). 6.95-7.08 (m, 3H), 6.02-6.05 (m, 1H), 5.83-5.85 (m, 1H), 5.52 (s, 1H), 5.39-5.44 (m, 2H), 5.30-5.32 (m, 1H), 5.22-5.24 (m, 1H), 5.06-5.08 (m, 1H). 4, 68-4.86 (m, 5H), 4.42-4.44 (m, 1H), 4.32-4.36 (m, 1H), 4.24-4.25 (m, 2H), 3.97-4.00 (m, 1H), 3.88-3.91 (m, 1H), 2.66-2.68 (m, 1H), 2.42-2.45 (m, 1H), 2.31-2.34 (m, 1H), 2.19-2.30 (m, 2H), 2.12-2.18 (m, 1H), 1.63-1.84 (m, 16H), 1.24-1.26 (m, 2H), 1.09-1.16 (m, 4H), 0.86-0.96 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6v: m/z calculated 1026.5. founded 1026.6.

EXAMPLE 21 Synthesis of Compound 6w

Compound 6w was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3v (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6w (75 mg, yield: 38%) was obtained.

¹H NMR for the product 6w (500 MHz, CDCl₃): δ 8.11 (m, 1H), 8.01-8.00 (m, 1H), 87.84-7.79 (m, 2H), 7.64-7.45 (m, 10H), 7.21-7.13 (m, 3H), 5.61-5.58 (m, 1H), 5.53-5.51 (m, 1H), 5.45-5.43 (m, 1H), 5.27-5.25 (m, 1H), 4.51-4.48 (m, 1H), 4.35-4.27 (m, 2H), 4.13-4.09 (m, 1H), 3.85-3.84 (m, 1H), 3.67 (s, 3H), 3.40 (s, 3H), 2.20-2.96 (m, 8H), 0.89-0.83 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6w: m/z calculated 965.4. founded 965.5.

EXAMPLE 22 Synthesis of Compound 6x

Compound 6x was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3w (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6x (68 mg, yield: 35%) was obtained.

¹H NMR for the product 6x (500 MHz, CDCl₃): δ 8.04-8.02 (m, 1H), δ7.90-7.88 (m, 1H), 7.68-7.52 (m, 11H), 7.36-7.32 (m, 2H), 7.22-7.24 (m, 2H), 5.55-5.48 (m, 3H). 5.28 (m, 2H). 4.42-4.34 (m, 2H), 3.88-3.86 (m, 2H), 3.71 (s, 6H), 2.40-2.01 (m, 8H), 0.92-0.89 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6x: m/z calculated 965.4. founded 965.5.

EXAMPLE 23 Synthesis of Compound 6y

Compound 6y was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3x (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6y (28 mg, yield: 19%) was obtained.

¹H NMR for the product 6y (500 MHz, CDCl₃): δ 7.68-7.47 (m, 7H), 7.33-7.18 (m, 3H). 5.54-5.53 (m, 1H), 5.35-5.25 (m, 2H), 4.35-4.30 (m, 1H), 3.87-3.85 (m, 1H), 3.76-3.69 (m, 6H), 3.30 (m, 1H), 2.91 (m, 1H), 2.38-2.35 (m, 2H), 2.34-1.92 (m, 7H). 1.38-1.20 (m, 12H), 0.95-0.85 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6y: m/z calculated 723.4. founded 723.5.

EXAMPLE 24 Synthesis of Compound 6z

Compound 6z was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3y (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6z (76 mg, yield: 50%) was obtained.

¹H NMR for the product 6z (500 MHz, CDCl₃): δ 7.76-7.56 (m, 7H), 7.34-7.21 (m, 3H), 5.51-5.26 (m, 3H), 4.34-4.33 (m, 1H), 3.84-3.60 (m, 7H), 3.51 (m, 1H), 2.76-2.74 (m, 1H), 2.40-2.33 (m, 2H), 2.38-1.95 (m, 13H), 1.26-1.23 (m, 4H), 0.93-0.86 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6z: m/z calculated 751.4. founded 751.5.

EXAMPLE 25 Synthesis of Compound 6aa

Compound 6aa was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3z (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6aa (52 mg, yield: 34%) was obtained.

¹H NMR for the product 6aa (500 MHz, CDCl₃): δ 7.82-7.49 (m, 6H). 7.34-7.19 (m, 4H). 5.54-5.49 (m, 1H), 5.36-5.27 (m, 1H), 4.37-4.28 (m, 1H), 3.57-3.55 (m, 6H), 2.98 (m, 1H), 2.34-2.33 (m, 2H), 2.27-1.57 (m, 12H), 1.44-1.21 (m, 8H), 0.94-0.87 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6aa: m/z calculated 765.4. founded 765.5.

EXAMPLE 26 Synthesis of Compound 6ab

Compound 6ab was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3aa (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ab (991 mg, yield: 65%) was obtained.

¹H NMR for the product 6ab (500 MHz, CDCl₃): δ 7.85-7.76 (m, 2H), 7.67-7.56 (m, 5H), 7.40-7.37 (m, 2H), 7.22-7.16 (m, 1H), 5.51-5.45 (m, 2H), 5.40-5.30 (m, 2H), 4.45-4.36 (m, 2H), 3.88-3.86 (m, 2H), 3.71 (s, 6H), 2.87-2.85 (m, 1H), 2.51-1.74 (m, 11H), 1.10-0.80 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6ab: m/z calculated 753.4. founded 753.5.

EXAMPLE 27 Synthesis of Compound 6ac

Compound 6ac was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3aa (0.2 mmol) and SM-4n (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ac (64 mg, yield: 42%) was obtained.

¹H NMR for the product 6ac (500 MHz, CDCl₃): δ 7.81-7.45 (m, 8H), 7.37-7.22 (m, 4H), 6.72-6.62 (m, 2H), 5.97-5.93 (m, 2H), 5.55-5.35 (m, 3H), 4.71-4.57 (m, 4H), 4.26-4.12 (m, 2H), 3.77-3.70 (m, 3H), 3.51-3.43 (m, 3H), 2.83 (m, 1H), 2.57-2.47 (m, 2H), 2.07-1.77 (m, 9H), 1.12-1.11 (m, 6H), 0.84-0.82 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6ac: m/z calculated 958.4. founded 958.5.

EXAMPLE 28 Synthesis of Compound 6ad

Compound 6ad was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3aa (0.20 mmol) and SM-4i (0.20 mmol) instead of SM-3a and SM-4i, a yellow solid 6ad (64 mg, yield: 33%) was obtained.

¹H NMR for the product 6ad (500 MHz, CDCl₃): δ 7.80-7.46 (m, 8H), 7.37-7.22 (m, 4H), 6.78-6.66 (m, 2H), 5.98-5.97 (m, 2H), 5.56-5.34 (m, 3H), 4.75-4.59 (m, 4H), 4.25-4.17 (m, 2H), 3.86-3.64 (m, 3H), 3.49-3.46 (m, 3H), 2.82 (m, 1H), 2.58-2.47 (m, 2H), 2.08-1.76 (m, 9H), 1.12-1.11 (m, 6H), 0.86-0.84 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6ad: m/z calculated 958.4. founded 958.5.

EXAMPLE 29 Synthesis of Compound 6ae

Compound 6ae was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3a (0.2 mmol) and SM-4ac (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ae (32 mg, yield: 17%) was obtained.

¹H NMR for the product 6ae (500 MHz, CDCl₃): δ 7.81-7.55 (m, 8H), 7.34-7.22 (m, 4H), 6.80-6.69 (m, 2H), 5.99-5.97 (m, 1H), 5.57-5.56 (m, 1H), 5.32-5.17 (m, 2H), 4.93-4.72 (m, 4H), 4.35-4.25 (m, 2H), 3.74-3.69 (m, 6H), 2.96 (m, 1H), 2.37-2.36 (m, 1H), 2.24-1.76 (m, 8H), 1.16-0.79 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6ae: m/z calculated 929.4. founded 929.5.

EXAMPLE 30 Synthesis of Compound 6af

Compound 6af was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3a (0.2 mmol) and SM-4ad (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6af (19 mg, yield: 10%) was obtained.

¹H NMR for the product 6af (500 MHz, CDCl₃): δ 7.77-7.54 (m, 8H), 7.28-7.22 (m, 2H), 6.73-6.68 (m, 2H), 6.00-5.98 (m, 2H), 5.61-5.46 (m, 2H), 5.35-5.22 (m, 2H), 4.85-4.75 (m, 4H), 4.365-4.10 (m, 2H), 3.72-3.70 (m, 6H), 2.95 (m, 1H), 2.39 (m, 1H). 2.03-1.81 (m, 8H), 1.10-0.90 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6af: m/z calculated 929.4. founded 929.5.

EXAMPLE 31 Synthesis of Compound 6ag

Compound 6ag was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ab (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ag (99 mg, yield: 65%) was obtained.

¹H NMR for the product 6ag (500 MHz, CDCl₃): δ 7.83-7.53 (m, 7H). 7.47-7.19 (m, 3H). 5.50-5.48 (m, 1H), 5.27-5.26 (m, 1H), 5.08-5.03 (m, 1H), 4.54-4.48 (m, 1H), 4.40-4.33 (m, 1H), 4.01-3.82 (m, 3H), 3.70 (m, 6H), 2.95-2.90 (m, 1H), 2.38-2.37 (m, 1H), 2.23-1.83 (m, 8H), 1.27-1.11 (m, 6H), 0.97-0.86 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6ag: m/z calculated 755.4. founded 755.5.

EXAMPLE 32 Synthesis of Compound 6ah

Compound 6ah was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ab (0.2 mmol) and SM-4n (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ah (22 mg, yield: 14%) was obtained.

¹H NMR for the product 6ah (500 MHz, CDCl₃): δ 7.80-7.59 (m, 8H), 7.27 (m, 2H), 6.71-6.65 (m, 2H), 5.96 (s, 2H), 5.46-5.38 (m, 3H), 5.08-5.03 (m, 1H), 4.68-4.53 (m, 5H), 3.79-3.70 (m, 3H), 3.57-3.50 (m, 3H), 2.91-2.84 (m, 2H), 2.15-1.88 (m, 10H), 1.26-1.11 (m, 6H), 0.93-0.86 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺]: m/z calculated 960.4. founded 960.5.

EXAMPLE 33 Synthesis of Compound 6ai

Compound 6ai was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ab (0.2 mmol) and SM-4i (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ai (38 mg, yield: 25%) was obtained.

¹H NMR for the product 6ai (500 MHz, CDCl₃): δ 7.80-7.58 (m, 8H), 7.28-7.23 (m, 2H). 6.78-6.66 (m, 2H), 5.98-5.97 (m, 2H), 5.47-5.37 (m, 3H), 5.08-5.04 (m, 1H), 4.75-4.53 (m, 5H), 4.24-4.21 (m, 2H), 3.79-3.65 (m, 3H), 3.57-3.49 (m, 3H), 2.92 (m, 1H), 2.57 (m, 1H), 2.15-1.73 (m, 8H), 1.28-1.11 (m, 6H), 0.83-0.75 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6ai: m/z calculated 960.4. founded 960.5.

EXAMPLE 34 Synthesis of Compound 6aj

Compound 6aj was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ab (0.2 mmol) and SM-4aa (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6aj (67 mg, yield: 43%) was obtained.

¹H NMR for the product 6aj (500 MHz, CDCl₃): δ 7.85-7.39 (m, 8H), 5.58-5.54 (m, 1H), 5.41-5.35 (m, 1H), 5.09-5.05 (m, 1H), 4.60 (m, 1H), 4.54-4.40 (m, 2H), 4.31-4.30 (m, 1H), 4.20-4.18 (m, 1H), 4.02 (m, 1H), 3.80 (m, 3H), 3.72-3.43 (m, 3H), 3.04-3.03 (m, 2H), 2.98-2.84 (m, 2H), 2.45 (m, 1H), 2.30 (m, 1H), 1.76-1.62 (m, 2H), 1.49-1.33 (m, 2H), 1.15-1.12 (m, 6H), 0.95-0.87 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6aj: m/z calculated 769.4. founded 769.5.

EXAMPLE 35 Synthesis of Compound 6ak

Compound 6ak was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ae (0.2 mmol) and SM-4n (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ak (yield: 51%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6ak: m/z calculated 970.4. founded 970.6.

EXAMPLE 36 Synthesis of Compound 6am

Compound 6am was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ae (0.2 mmol) and SM-4ad (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6am (yield: 53%) was obtained.

Confirmed by MS. ESI-MS [(M+H)⁺] for 6am: m/z calculated 955.4. founded 955.6.

EXAMPLE 37 Synthesis of Compound 6an

Compound 6an was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ae (0.2 mmol) and SM-4i (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6an (yield: 52%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺]: m/z calculated 970.4. founded 970.6.

EXAMPLE 38 Synthesis of Compound 6ap

Compound 6ap was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ae (0.2 mmol) and SM-4ac (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ap (yield: 53%) was obtained.

Confirmed by MS. ESI-MS [(M+H)⁺] for 6ap: m/z calculated 955.4. founded 955.6.

EXAMPLE 39 Synthesis of Compound 6aq

Compound 6aq was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3af (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6aq (yield: 53%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6aq: m/z calculated 885.4. founded 885.5.

EXAMPLE 40 Synthesis of Compound 6ar

Compound 6ar was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ag (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ar (yield: 55%) was obtained.

¹H-NMR of the product 6ar (500 MHz, CDCl₃): δ 7.53-7.76 (m, 9H), 7.18-7.29 (m, 3H), 6.96-7.08 (m, 2H), 5.60-5.70 (m, 2H), 5.20-5.46 (m, 4H), 4.80-5.03 (m, 5H), 4.24-4.36 (m, 2H), 3.86-4.11 (m, 2H), 3.68-3.72 (m, 6H), 2.92 (m, 1H), 2.38 (m, 1H), 2.22 (m, 1H), 2.00-2.11 (m, 4H), 0.88-0.93 (m, 12H). ESI-MS [(M+H)⁺] for 6ar: m/z calculated 903.4. found 903.5.

EXAMPLE 41 Synthesis of Compound 6as

Compound 6as was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ah (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6as (yield: 54%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6as: m/z calculated 903.4. founded 903.5.

EXAMPLE 42 Synthesis of Compound 6at

Compound 6at was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ai (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6at (yield: 51%) was obtained.

Confirmed by MS. ESI-MS [(M+H)⁺] for 6at: m/z calculated 919.4. founded 919.5.

EXAMPLE 43 Synthesis of Compound 6au

Compound 6au was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3aj (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6au (yield: 52%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6au: m/z calculated 919.4. founded 919.5.

EXAMPLE 44 Synthesis of Compound 6av

Compound 6av was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3am (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6av (yield: 63%) was obtained.

¹H-NMR of the product 6av (500 MHz, CDCl₃): δ 7.54-7.80 (m, 9H), 7.17-7.22 (m, 3H), 6.76-6.85 (m, 3H), 5.60-5.72 (m, 2H), 5.19-5.44 (m, 4H), 4.82-4.92 (m, 5H), 3.97-4.34 (m, 4H), 3.79-3.82 (m, 3H), 3.68-3.73 (m, 6H), 2.95 (m, 1H), 2.37 (m, 1H), 2.20-2.21 (m, 1H), 1.98-2.11 (m, 4H), 0.88-0.95 (m, 12H). ESI-MS [(M+H)⁺] for 6av: m/z calculated 915.4. found 915.5.

EXAMPLE 45 Synthesis of Compound 6aw

Compound 6aw was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ak (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6aw (yield: 61%) was obtained.

¹H-NMR of the product 6aw (500 MHz, CDCl₃): δ 7.48-7.80 (m, 9H), 7.16-7.25 (m, 4H), 6.83-6.84 (m, 1H). 6.72-6.73 (m, 1H), 5.70-5.78 (m, 2H), 5.22-5.41 (m, 4H), 4.74-4.98 (m, 5H), 4.28-4.30 (m, 2H), 4.01-4.13 (m, 2H), 3.81 (s, 3H), 3.64-3.66 (m, 6H), 2.92 (m, 1H), 2.38 (m, 1H), 2.17-2.18 (m, 1H), 1.94-2.07 (m, 4H), 0.85-0.91 (m, 12H). ESI-MS [(M+H)⁺] for 6aw: m/z calculated 915.4. found 915.5.

EXAMPLE 46 Synthesis of Compound 6ax

Compound 6ax was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3an (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ax (yield: 54%) was obtained.

¹H-NMR of the product 6ax (500 MHz, CDCl₃): δ 7.54-7.84 (m, 9H), 7.23 (s, 1H), 7.20 (s, 1H), 6.79 (s, 2H), 6.74 (s, 1H), 6.81-6.87 (m, 2H), 5.58-5.70 (m, 2H), 5.46 (m, 1H), 5.19-5.34 (m, 3H), 4.72-4.92 (m, 5H), 3.97-4.35 (m, 4H), 3.86-3.89 (m, 6H), 3.69-3.74 (m, 6H), 2.96 (m, 1H), 2.38 (m, 1H), 2.22 (m, 1H), 1.99-2.12 (m, 4H), 0.89-0.96 (m, 12H). ESI-MS [(M+H)⁺] for 6ax: m/z calculated 945.4. found 945.5.

EXAMPLE 47 Synthesis of Compound 6ay

Compound 6ay was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ac (0.2 mmol) and SM-4ag (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ay (yield: 53%) was obtained.

Confirmed by MS. ESI-MS [(M+H)⁺] for 6ay: m/z calculated 963.4. founded 963.5.

EXAMPLE 48 Synthesis of Compound 6az

Compound 6az was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3n (0.2 mmol) and SM-4ae (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6az (yield: 56%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6az: m/z calculated 956.4. founded 956.5.

EXAMPLE 49 Synthesis of Compound 6ba

Compound 6ba was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3a (0.5 mmol) and SM-4b (0.5 mmol) instead of SM-3a and SM-4i, a yellow solid 6ba (118 mg, yield: 32%) was obtained.

¹H NMR for the product 6ba (500 MHz, CDCl₃): δ 7.59-7.18 (m, 10H), 6.26 (m, 1H). 6.09 (m, 1H), 6.00 (m, 1H), 5.50 (m, 1H), 5.27 (m, 1H), 4.76 (m, 1H), 4.52 (m, 1H), 4.36 (m, 1H), 4.30 (m, 1H), 3.86 (m, 1H), 3.71 (s, 6H), 2.38-2.00 (m, 6H), 0.91 (d. 6H), 0.89 (d. 6H). ESI-MS [(M+H)⁺] for 6dx: m/z calculated 737.4. found 737.5.

EXAMPLE 50 Synthesis of Compound 6bb

Compound 6bb was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3e (0.2 mmol) and SM-4f (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bb (47 mg, yield: 27%) was obtained.

¹H NMR for the product 6bb (500 MHz, CDCl₃): δ 7.57-7.72 (m, 4H), 7.16-7.23 (m, 2H), 6.29 (s, 1H), 6.00-6.07 (m, 2H), 5.24-5.36 (m, 3H), 4.75, 4.76 (d, 1H), 4.45-4.57 (m, 2H), 4.27-4.36 (m, 2H), 3.88 (s, 1H), 3.67-3.68 (m, 1H), 2.20-2.34 (m, 2H), 1.99-2.09 (m, 2H), 1.46 (s, 18H), 0.93 (m, 18H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6bb: m/z calculated 849.5. founded 849.6.

EXAMPLE 51 Synthesis of Compound 6bc

Compound 6bc was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3a (0.2 mmol) and SM-4d (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bc (32 mg, yield: 20%) was obtained.

¹H NMR for the product 6bc (500 MHz, CDCl₃): δ 7.46-7.54 (m, 4H), 7.15-7.24 (m, 2H), 6.29 (s, 1H), 6.07-6.08 (m, 1H), 6.00 (s, 1H), 5.50-5.52 (m, 1H), 5.23-5.27 (m, 2H), 4.69-4.72 (m, 1H), 4.25-4.47 (m, 3H), 3.83-3.86 (m, 1H), 3.70 (s, 3H), 2.34-2.38 (m, 1H), 1.95-2.23 (m, 5H), 1.46 (s, 6H), 0.88-0.93 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6bc: m/z calculated 779.4. founded 779.5.

EXAMPLE 52 Synthesis of Compound 6bd

Compound 6bd was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3b (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bd (yield: 33%) was obtained.

¹H NMR for the product 6bd (500 MHz, CDCl₃): δ 7.77-7.80 (m, 2H), 7.56-7.60 (m, 4H), 7.20-7.23 (m, 2H), 6.30-6.33 (m, 2H), 6.08-6.09 (m, 2H), 5.99 (s, 2H), 5.34-5.39 (m, 2H), 4.72-4.74 (m, 2H), 4.42-4.45 (m, 2H), 4.27-4.30 (m, 2H), 3.71 (s, 6H), 1.96-2.01 (m, 2H), 1.25-1.34 (m, 6H), 0.87-0.90 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6bd: m/z calculated 735.4. founded 735.4.

EXAMPLE 53 Synthesis of Compound 6be

Compound 6be was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3d (0.2 mmol) and SM-4d (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6be (yield: 42%) was obtained.

¹H NMR for the product 6be (500 MHz, CDCl₃): δ 7.70-7.76 (m, 2H), 7.47-7.60 (m, 4H), 7.21-7.25 (m, 2H), 6.28-6.32 (m, 2H), 6.07-6.08 (m, 2H), 6.01 (s, 2H), 5.21-5.23 (m, 2H), 4.69-4.72 (m, 2H), 4.44-4.47 (m, 2H), 4.25-4.29 (m, 2H). 1.94-1.99 (m, 2H), 1.46 (s, 18H). 0.82-0.89 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6be: m/z calculated 819.5. founded 819.5.

EXAMPLE 54 Synthesis of Compound 6bf

Compound 6bf was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3h (0.2 mmol) and SM-4h (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bf (yield: 34%) was obtained.

¹H NMR for the product 6bf (500 MHz, CDCl₃): δ 7.47-7.63 (m, 6H), 7.15-7.23 (m, 2H). 7.21-7.24 (m, 2H), 6.07-6.08 (m, 2H), 6.00 (s, 2H), 5.30-5.32 (m, 2H), 5.08-5.09 (m, 2H), 4.73-4.76 (m, 2H), 4.48-4.51 (m, 2H), 4.27-4.30 (m, 2H), 1.94-2.00 (m, 2H), 1.83-1.86 (m, 4H), 1.71 (s, 8H), 1.58 (s, 4H), 0.90-0.91 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6bf: m/z calculated 843.5. founded 843.6.

EXAMPLE 55 Synthesis of Compound 6bg

Compound 6bg was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3g (0.2 mmol) and SM-4h (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bg (yield: 15%) was obtained.

¹H NMR for the product 6bg (400 MHz, CD₃OD): δ 7.38-7.34 (m, 1H), 7.00-6.96 (m, 2H), 6.11-6.03 (m, 1H), 5.43-5.39 (m, 1H), 5.29-5.27 (m, 1H), 4.65-4.64 (m, 2H), 4.62 (s, 2H), 4.57 (s, 2H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6bg: m/z calculated 845.5. founded 845.6.

EXAMPLE 56 Synthesis of Compound 6bh

Compound 6bh was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3x (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bh (yield: 57.5%) was obtained.

¹H NMR for the product 6bh (500 MHz, CDCl₃): δ 7.66-7.52 (m, 8H), 7.20 (m, 2H), 6.23 (m, 1H), 6.23 (m, 1H), 6.06-6.05 (m, 1H), 5.98 (m, 1H), 5.73 (m, 1H), 5.53-5.52 (m, 1H), 5.35 (m, 1H), 4.74-4.71 (m, 1H), 4.49-4.47 (m, 1H), 4.29-4.26 (m, 1H), 3.77-3.69 (m, 6H), 2.33-2.32 (m, 1H), 2.09-1.95 (m, 4H), 1.32-1.24 (m, 4H), 0.91-0.80 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6bh: m/z calculated 721.3. founded 721.5.

EXAMPLE 57 Synthesis of Compound 6bi

Compound 6bi was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3y (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bi (yield: 43%) was obtained.

¹H NMR for the product 6bi (500 MHz, CDCl₃): δ 7.76-7.55 (m, 8H), 7.26-7.23 (m, 2H), 6.29-6.28 (m, 1H), 6.08-6.07 (m, 1H), 5.99 (m, 1H), 5.51-5.49 (m, 1H), 5.37 (m, 1H), 4.75-4.72 (m, 1H), 4.47-4.44 (m, 1H), 4.30-4.27 (m, 1H), 3.72-3.70 (m, 6H), 2.77-2.74 (m, 1H). 2.39-2.34 (m, 1H), 2.15-1.73 (m, 10H), 1.26 (m, 1H), 0.90-0.85 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6bi: m/z calculated 749.4. founded 749.5.

EXAMPLE 58 Synthesis of Compound 6bj

Compound 6bj was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3z (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bj (yield: 33%) was obtained.

¹H NMR for the product 6bj (500 MHz, CDCl₃): δ 7.75-7.46 (m, 6H), 7.35-7.24 (m, 4H), 6.08-5.99 (m, 1H), 5.52-5.48 (m, 1H), 4.75-4.72 (m, 1H), 4.47-4.44 (m, 1H), 4.30-4.28 (m, 1H), 3.76-3.58 (m, 6H), 2.39 (m, 2H), 2.14-1.55 (m, 11H), 1.26 (m, 6H), 0.94-0.88 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6bj: m/z calculated 763.4. founded 763.5.

EXAMPLE 59 Synthesis of Compound 6bk

Compound 6bk was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3aa (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bk (yield: 61%) was obtained.

¹H NMR for the product 6bk (500 MHz, CDCl₃): δ 7.81-7.52 (m, 6H), 7.38-7.20 (m, 4H), 6.09 (m, 1H), 6.0 (m, 1H), 5.43 (m, 1H), 4.73-4.70 (m, 1H), 4.48-4.43 (m, 1H), 4.32-4.29 (m, 1H), 3.70-3.63 (m, 6H), 2.85-2.83 (m, 1H), 2.09-1.48 (m, 11H), 1.11 (m, 6H), 0.92-0.85 (m. 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6bk: m/z calculated 751.3. founded 751.5.

EXAMPLE 60 Synthesis of Compound 6bm

Compound 6bm was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ab (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bm (yield: 54%) was obtained.

¹H NMR for the product 6bm (500 MHz, CDCl₃): δ 7.76-7.42 (m, 9H), 7.28-7.21 (m, 1H), 6.24 (m, 1H), 6.10-6.09 (m, 1H), 5.99 (m, 1H), 5.45-5.46 (m, 1H), 5.13-5.04 (m, 1H), 4.74-4.71 (m, 1H), 4.53-4.52 (m, 2H), 4.41-4.28 (m, 2H), 4.14-4.00 (m, 2H), 3.70 (m, 6H), 2.94 (m, 1H), 2.11-1.99 (m, 3H), 1.27-1.12 (m, 6H), 0.95-0.87 (m, 6H). Confirmed by MS. ESI-MS [(M+H)⁺] for 6bm: m/z calculated 753.4. founded 753.5.

EXAMPLE 61 Synthesis of Compound 6bn

Compound 6bn was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cs (0.2 mmol) and SM-4af (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bn (yield: 61%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6bn: m/z calculated 958.4. founded 958.5.

EXAMPLE 62 Synthesis of Compound 6 bp

Compound 6 bp was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ap (0.2 mmol) and SM-4bi (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6 bp (yield: 56%) was obtained.

Confirmed by MS. ESI-MS [(M+H)⁺] for 6 bp: m/z calculated 992.4. founded 992.5.

EXAMPLE 63 Synthesis of Compound 6bq

Compound 6bq was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3aq (0.2 mmol) and SM-4bj (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bq (yield: 53%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6bq: m/z calculated 835.4. founded 835.5.

EXAMPLE 64 Synthesis of Compound 6br

Compound 6br was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ap (0.2 mmol) and SM-4bk (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6br (yield: 52%) was obtained.

Confirmed by MS. ESI-MS [(M+H)⁺] for 6br: m/z calculated 1042.4. founded 1042.5.

EXAMPLE 65 Synthesis of Compound 6bs

Compound 6bs was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ar (0.2 mmol) and SM-4bj (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bs (yield: 54%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6bs: m/z calculated 1027.4. founded 1027.5.

EXAMPLE 66 Synthesis of Compound 6bt

Compound 6bt was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3as (0.2 mmol) and SM-4bi (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bt (yield: 52%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6bt: m/z calculated 968.4. founded 968.5.

EXAMPLE 67 Synthesis of Compound 6bu

Compound 6bu was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3at (0.2 mmol) and SM-4n (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bu (yield: 56%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6bu: m/z calculated 994.4. founded 994.5.

EXAMPLE 68 Synthesis of Compound 6bv

Compound 6bv was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3at (0.2 mmol) and SM-4ad (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bv (yield: 53%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6bv: m/z calculated 979.4. founded 979.5.

EXAMPLE 69 Synthesis of Compound 6bw

Compound 6bw was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3av (0.2 mmol) and SM-4ad (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bw (yield: 52%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6bw: m/z calculated 979.4. founded 979.5.

EXAMPLE 70 Synthesis of Compound 6bx

Compound 6bx was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ay (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bx (yield: 54%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6bx: m/z calculated 771.4. founded 771.4.

EXAMPLE 71 Synthesis of Compound 6by

Compound 6by was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3b (0.2 mmol) and SM4ag (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6by (yield: 56%) was obtained.

Confirmed by MS. ESI-MS [(M+H)⁺] for 6by: m/z calculated 771.4. founded 771.4.

EXAMPLE 72 Synthesis of Compound 6bz

Compound 6bz was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ax (0.2 mmol) and SM-4ah (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6bz (yield: 61%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6bz: m/z calculated 805.3. founded 805.4.

EXAMPLE 73 Synthesis of Compound 6ca

Compound 6ca was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ay (0.2 mmol) and SM-4ah (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ca (yield: 53%) was obtained.

Confirmed by MS. ESI-MS [(M+H)⁺] for 6ca: m/z calculated 803.3. founded 803.4.

EXAMPLE 74 Synthesis of Compound 6cb

Compound 6cb was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3at (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6cb (yield: 510/0) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6cb: m/z calculated 787.4. founded 787.5.

75

EXAMPLE 75 Synthesis of Compound 6cc

Compound 6cc was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3bz (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6cc (yield: 58%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6cc: m/z calculated 787.4. founded 787.5.

EXAMPLE 76 Synthesis of Compound 6cd

Compound 6cd was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ci (0.2 mmol) and SM-4bd (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6cd (yield: 43%) was obtained.

Confirmed by MS. ESI-MS [(M+H)⁺] for 6cd: m/z calculated 880.4. founded 880.5.

EXAMPLE 77 Synthesis of Compound 6ce

Compound 6ce was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3bb (0.2 mmol) and SM-4ai (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ce (yield: 57%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6ce: m/z calculated 831.4. founded 831.5.

EXAMPLE 78 Synthesis of Compound 6cf

Compound 6cf was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3bd (0.2 mmol) and SM-4aj (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6cf (yield: 56%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6cf: m/z calculated 803.3. founded 803.4.

EXAMPLE 79 Synthesis of Compound 6cg

Compound 6cg was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3bg (0.2 mmol) and SM-4ak (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6cg (yield: 52%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6cg: m/z calculated 763.4. founded 763.5.

EXAMPLE 80 Synthesis of Compound 6ch

Compound 6ch was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3bi (0.2 mmol) and SM-4am (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ch (yield: 53%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6ch: m/z calculated 735.4. founded 735.5.

EXAMPLE 81 Synthesis of Compound 6ci

Compound 6ci was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3bg (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ci (yield: 53%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6ci: m/z calculated 750.4. founded 750.5.

EXAMPLE 82 Synthesis of Compound 6cj

Compound 6cj was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3bi (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6cj (yield: 59%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6cj: m/z calculated 736.4. founded 736.5.

EXAMPLE 83 Synthesis of Compound 6ck

Compound 6ck was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3bi (0.2 mmol) and SM-4am (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ck (yield: 53%) was obtained.

Confirmed by MS, ESI-MS [(M+H)⁺] for 6ck: m/z calculated 735.4. founded 735.5.

EXAMPLE 84 Synthesis of Compound 6cm

Compound 6cm was prepared by the same coupling reaction procedure as in example 1, in which the SM-3a (0.2 mmol) and SM-4an (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6cm was obtained as a yellow solid, yield: 54%.

¹H-NMR of the product 6cm (500 MHz, CDCl₃): δ 7.74-7.80 (m, 1H), 7.53-7.62 (m, 8H), 7.26-7.28 (m, 3H), 7.18-7.22 (m, 3H), 5.56-5.67 (m, 2H), 5.44 (m, 1H), 4.74-4.94 (m, 5H), 4.34 (m, 1H), 4.23 (m, 1H), 4.08 (m, 1H), 3.85 (m, 1H), 3.67-3.73 (m, 6H), 2.92 (m, 1H), 2.37 (m, 1H), 2.22 (m, 1H), 2.00-2.11 (m, 4H), 0.90-0.91 (m, 12H). ESI-MS [(M+H)⁺] for 6cm: m/z calculated 919.4. found 919.5.

EXAMPLE 85 Synthesis of Compound 6cq

Compound 6cq was prepared by the same coupling reaction procedure as in example 1, in which the SM-3a (0.2 mmol) and SM-4ar (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6cq was obtained as a yellow solid, yield: 43%.

¹H-NMR of the product 6cq (500 MHz, CDCl₃): δ 7.46-7.75 (m, 9H), 7.12-7.30 (m, 3H). 6.81-6.87 (m, 2H), 5.64-5.74 (m, 2H), 5.17-5.41 (m, 4H), 4.56-4.93 (m, 5H), 3.94-4.30 (m, 4H), 3.81-3.85 (m, 6H), 3.63-3.65 (m, 6H), 2.83 (m, 1H), 2.33 (m, 1H), 2.17 (m, 1H), 1.96-2.07 (m, 4H), 0.86-0.89 (m, 12H). ESI-MS [(M+H)⁺] for 6cq: m/z calculated 945.5. found 945.7.

EXAMPLE 86 Synthesis of Compound 6cu

Compound 6cu was prepared by the same coupling reaction procedure as in example 1, followed by cleavage of Boc group and neutralization workup, in which SM-3a (1.45 mmol) and SM-4av (1.45 mmol) were used instead of SM-3a and SM-4i. The coupling product first obtained (yield: 25%) was subsequently treated with 10 mL 3N HCl/Et₂O at room temperature, followed by basification and preparative TLC purification to afford compound 6cu (100 mg) as a yellow solid, yield: 37%.

¹H-NMR of the product 6cu (500 MHz, CDCl₃): δ 7.50-7.78 (m, 9H), 7.02-7.35 (m, 3H), 5.67 (m, 2H), 5.13-5.26 (m, 2H), 4.69-4.75 (m, 2H), 4.35-4.41 (m, 2H), 4.13-4.14 (m, 1H), 3.88 (m, 1H), 3.71 (s, 6H), 3.35 (m, 1H), 2.18-2.39 (m, 2H), 2.00-2.11 (m, 4H), 0.91 (s, 12H). ESI-MS [(M+H)⁺] for 6cu: m/z calculated 740.4. found 740.5.

EXAMPLE 87 Synthesis of Compound 6cv

Compound 6cv was prepared by prepared by the same coupling reaction procedure as in example 1, followed by cleavage of Boc group and neutralization workup, in which SM-3b (0.34 mmol) and SM-4av (0.34 mmol) were used instead of SM-3a and SM-4i. The coupling product first obtained was subsequently treated with 10 mL HCl/Et₂O (3N) at room temperature, followed by basification and preparative TLC purification to afford compound 6cv (80 mg) as a yellow solid, yield after two steps: 32%.

ESI-MS [(M+H)⁺] for 6cv: m/z calculated 738.4. found 738.5.

EXAMPLE 88 Synthesis of Compound 6cw

Compound 6cw was prepared by the same coupling reaction procedure as in example 1, in which SM-3b (0.34 mmol) and SM-4av (0.34 mmol) were used instead of SM-3a and SM-4i, and the product 6cw was obtained as a yellow solid, yield: 35%.

ESI-MS [(M+H)⁺] for 6cw: m/z calculated 838.4. found 838.6.

EXAMPLE 89 Synthesis of Compound 6cx

Compound 6cx was prepared by the same coupling reaction procedure as in example 1, followed by cleavage of Boc group, in which SM-3b (0.2 mmol) and SM-4aw (0.2 mmol) were used instead of SM-3a and SM-4i. The coupling product first obtained (13 mg, yield: 10%) was subsequently taken of 10 mg and treated with 10 mL 3N HCl/Et₂O at room temperature, followed by vacuum concentration to afford product 6cx (32%).

ESI-MS [(M+H)⁺] for 6cx: m/z calculated 778.5. found 778.6.

EXAMPLE 90 Synthesis of Compound 6cy

Compound 6cy was prepared by the same coupling reaction procedure as in example 1, in which SM-3b (0.2 mmol) and SM-4aw (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6cy was obtained as a yellow solid, yield: 23%.

ESI-MS [(M+H)⁺] for 6cy: m/z calculated 878.5. found 878.6.

EXAMPLE 91 Synthesis of Compound 6cz

Compound 6cz was prepared by the same coupling reaction procedure as in example 1, in which SM-3bj (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6cz was obtained as a yellow solid, yield: 29%.

¹H-NMR of the product 6cz (500 MHz, CDCl₃): δ 7.62-7.78 (m, 10H), 5.98-6.09 (m, 2H). 5.43-5.59 (m, 2H), 4.49-4.60 (m, 4H), 3.70-3.75 (m, 8H), 3.01 (s, 3H), 2.78 (m, 1H), 0.89-0.91 (m, 12H). ESI-MS [(M+H)⁺] for 6cz: m/z calculated 816.3. found 816.5.

EXAMPLE 92 Synthesis of Compound 6da

Compound 6da was prepared by the same coupling reaction procedure as in example 1, in which SM-3bk (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6da was obtained as a yellow solid, yield: 32%.

ESI-MS [(M+H)⁺] for 6da: m/z calculated 842.4. found 842.5.

EXAMPLE 93 Synthesis of Compound 6db

Compound 6db was prepared by the same coupling reaction procedure as in example 1, in which SM-3bm (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6db was obtained as a yellow solid, yield: 22%.

ESI-MS [(M+H)⁺] for 6db: m/z calculated 796.4. found 796.6.

EXAMPLE 94 Synthesis of Compound 6dc

Compound 6de was prepared by the same coupling reaction procedure as in example 1, in which SM-3bn (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dc was obtained as a yellow solid, yield: 33%.

ESI-MS [(M+H)⁺] for 6dc: m/z calculated 824.4. found 824.5.

EXAMPLE 95 Synthesis of Compound 6dd

Compound 6dd was prepared by the same coupling reaction procedure as in example 1, in which SM-3 bp (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dd was obtained as a yellow solid, yield: 28%.

ESI-MS [(M+H)⁺] for 6dd: m/z calculated 844.4. found 844.5.

EXAMPLE 96 Synthesis of Compound 6de

Compound 6de was prepared by the same coupling reaction procedure as in example 1, in which SM-3bf (0.2 mmol) and SM-4a (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6de was obtained as a yellow solid, yield: 35%.

¹H-NMR of the product 6de (500 MHz, CDCl₃): δ 7.81 (m, 1H), 7.53-7.59 (m, 8H), 7.34 (s, 1H), 7.24 (s, 1H), 7.19 (s, 1H), 5.55-5.56 (d, J=8.5 Hz, 1H), 5.10-5.12 (d, J=8.5 Hz, 1H), 4.48-4.51 (t, J=7.5 Hz, 1H), 4.33-4.36 (m, 1H), 3.97 (m, 1H), 3.85 (m, 1H), 3.70 (s, 3H), 3.45 (m, 1H), 3.14 (m, 1H), 2.95 (s, 6H). 2.34-2.39 (m, 2H), 2.19-2.24 (m, 2H). 1.97-2.10 (m. 6H), 0.86-0.91 (m, 12H). ESI-MS [(M+H)⁺] for 6de: m/z calculated 752.4. found 752.5.

EXAMPLE 97 Synthesis of Compound 6df

Compound 6df was prepared by the same coupling reaction procedure as in example 1, in which SM-3bf (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6df was obtained as a yellow solid, yield: 35%.

¹H-NMR of the product 6df (500 MHz, CDCl₃): δ 7.82-7.86 (m, 1H), 7.54-7.68 (m, 8H), 7.34 (s, 1H), 7.19-7.23 (m, 2H), 6.24-6.28 (m, 1H), 5.98-6.08 (m, 2H), 5.44-5.53 (m, 1H), 5.26 (m, 1H), 5.08-5.09 (m, 1H), 4.71 (m, 1H), 4.49-4.51 (m, 1H), 4.28-4.34 (m, 1H), 3.94-3.95 (m, 1H), 3.70 (s, 3H), 3.43 (m, 1H), 3.15 (m, 1H), 2.92 (s, 6H), 1.97-2.20 (m, 6H), 1.05-1.10 (m, 6H), 0.88 (s, 6H). ESI-MS [(M+H)⁺] for 6df: m/z calculated 750.4. found 750.5.

EXAMPLE 98 Synthesis of Compound 6dg

Compound 6dg was prepared by the same coupling reaction procedure as in example 1, in which SM-3b (0.2 mmol) and SM-4ax (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dg was obtained as a yellow solid, yield: 36%.

¹H-NMR of the product 6dg (500 MHz, CDCl₃): δ 7.10-7.71 (m, 17H), 5.97-6.15 (m, 3H), 5.41-5.55 (m, 3H), 4.73 (m, 1H), 4.48-4.55 (m, 1H), 4.26 (m, 1H), 4.03 (m, 1H), 3.69 (s, 3H), 3.30 (m, 1H), 2.72 (m, 1H), 2.44 (s. 3H), 1.97-2.27 (m, 6H), 0.88-0.99 (m, 6H). ESI-MS [(M+H)⁺] for 6dg: m/z calculated 770.4. found 770.5.

EXAMPLE 99 Synthesis of Compound 6dh

Compound 6dh was prepared by the same coupling reaction procedure as in example 1, in which SM-3bq (0.2 mmol) and SM-4a (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dh was obtained as a yellow solid, yield: 22%.

ESI-MS [(M+H)⁺] for 6dh: m/z calculated 763.4. found 763.5.

EXAMPLE 100 Synthesis of Compound 6di

Compound 6di was prepared by the same coupling reaction procedure as in example 1, in which SM-3br (0.2 mmol) and SM-4a (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6di was obtained as a yellow solid, yield: 38%.

ESI-MS [(M+H)⁺] for 6di: m/z calculated 777.4. found 777.4.

EXAMPLE 101 Synthesis of Compound 6dj

Compound 6dj was prepared by the same coupling reaction procedure as in example 1, in which SM-3bs (0.2 mmol) and SM-4a (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dj was obtained as a yellow solid, yield: 46%.

¹H-NMR of the product 6dj (500 MHz, CDCl₃): δ 7.59-7.47 (m, 10H), 6.26 (m, 1H), 6.08 (m, 1H), 5.99 (m, 1H), 5.26 (s, 1H), 4.77 (m, 1H), 4.54 (m, 1H), 4.35 (m, 1H), 4.28 (m, 1H), 3.87 (m, 1H), 3.73 (s, 6H), 2.39 (m, 2H), 2.21-1.69 (m, 14H), 1.26 (d, 6H). ESI-MS [(M+H)⁺] for 6dj: m/z calculated 777.4. found 777.5.

EXAMPLE 102 Synthesis of Compound 6dk

Compound 6dk was prepared by the same coupling reaction procedure as in example 1, in which SM-3br (0.2 mmol) and SM-4ay (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dk was obtained as a yellow solid, yield: 36%.

ESI-MS [(M+H)⁺] for 6dk: m/z calculated 817.4. found 817.6.

EXAMPLE 103 Synthesis of Compound 6dm

Compound 6dm was prepared by the same coupling reaction procedure as in example 1, in which SM-3br (0.2 mmol) and SM-4az (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dm was obtained as a yellow solid, yield: 38%.

ESI-MS [(M+H)⁺] for 6dm: m/z calculated 815.4. found 815.5.

EXAMPLE 104 Synthesis of Compound 6dn

Compound 6dn was prepared by the same coupling reaction procedure as in example 1, in which SM-3bq (0.2 mmol) and SM-4ay (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dn was obtained as a yellow solid, yield: 30%.

ESI-MS [(M+H)⁺] for 6dn: m/z calculated 803.4. found 803.5.

EXAMPLE 105 Synthesis of Compound 6dp

Compound 6dp was prepared by the same coupling reaction procedure as in example 1, in which SM-3bq (0.2 mmol) and SM-4ba (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dp was obtained as a yellow solid, yield: 28%.

¹H-NMR of the product 6dp (500 MHz, CDCl₃): δ 8.02 (s, 1H), 7.85-7.55 (m, 9H), 6.34 (m, 1H), 6.09 (m, 1H), 5.99 (m, 1H), 5.42 (m, 1H), 5.36 (m, 1H), 4.81 (m, 1H), 4.44 (m, 1H), 4.38 (m, 1H), 3.90 (m, 1H), 3.71 (s, 6H), 3.50 (m, 1H), 2.34-2.01 (m, 16H). ESI-MS [(M+H)⁺] for 6dp: m/z calculated 789.4. found 789.5.

EXAMPLE 106 Synthesis of Compound 6dq

Compound 6dq was prepared by the same coupling reaction procedure as in example 1, in which SM-3bt (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dq was obtained as a yellow solid, yield: 36%.

¹H-NMR of the product 6dq (500 MHz, CDCl₃): δ 7.53-7.22 (m, 8H), 6.21 (m, 1H), 6.10 (m, 1H), 6.03 (m, 1H), 5.46 (m, 1H). 5.39 (m, 1H), 4.74 (m, 1H), 4.60 (m, 1H), 4.32 (m, 1H), 4.21 (m, 1H), 3.99 (m, 1H), 3.86 (m, 1H), 3.72 (s, 3H), 3.69 (s, 3H), 2.62 (m, 1H), 2.44 (m, 1H), 2.06-1.72 (m, 6H), 1.26 (d, 12H). ESI-MS [(M+H)⁺] for 6dq: m/z calculated 753.4. found 753.5.

EXAMPLE 107 Synthesis of Compound 6dr

Compound 6dr was prepared by the same coupling reaction procedure as in example 1, in which SM-3bu (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dr was obtained as a yellow solid, yield: 33%.

ESI-MS [(M+H)⁺] for 6dr: m/z calculated 753.4. found 753.5.

EXAMPLE 108 Synthesis of Compound 6ds

Compound 6ds was prepared by the same coupling reaction procedure as in example 1, in which SM-3bv(0.2 mmol) and SM-4a (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6ds was obtained as a yellow solid, yield: 38%.

ESI-MS [(M+H)⁺] for 6ds: m/z calculated 797.4. found 797.5.

EXAMPLE 109 Synthesis of Compound 6dt

Compound 6dt was prepared by the same coupling reaction procedure as in example 1, in which SM-3bv (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dt was obtained as a yellow solid, yield: 41%.

ESI-MS [(M+H)⁺] for 6dt: m/z calculated 795.4. found 795.5.

EXAMPLE 110 Synthesis of Compound 6du

Compound 6du was prepared by the same coupling reaction procedure as in example 1, in which SM-3bw (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6du was obtained as a yellow solid, yield: 39%.

¹H-NMR of the product 6du (500 MHz, CDCl₃): δ 7.16-7.82 (m, 15H). 5.98-6.26 (m, 3H), 5.35-5.53 (m, 1H), 4.71-4.74 (m, 1H), 4.48-4.51 (m, 1H), 3.91-4.04 (m, 6H), 3.62-3.69 (m, 8H), 2.47-2.38 (m, 1H). 2.04-2.08 (m, 1H), 1.69-2.00 (m, 1H), 1.05-0.87 (m, 6H). ESI-MS [(M+H)⁺] for 6du: m/z calculated 829.4. found 829.5.

EXAMPLE 111 Synthesis of Compound 6dv

Compound 6dv was prepared by the same coupling reaction procedure as in example 1, in which SM-3bw (0.2 mmol) and SM-4ah (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dv was obtained as a yellow solid, yield: 34%.

ESI-MS [(M+H)⁺] for 6dv: m/z calculated 863.3. found 863.5.

EXAMPLE 112 Synthesis of Compound 6dw

Compound 6dw was prepared by the same coupling reaction procedure as in example 1, in which SM-3bv (0.2 mmol) and SM-4ah (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dv was obtained as a yellow solid, yield: 37%.

ESI-MS [(M+H)⁺] for 6dw: m/z calculated 829.4. found 829.4.

EXAMPLE 113 Synthesis of Compound 6dy

Compound 6dy was prepared by the same coupling reaction procedure as in example 1, in which SM-3ay (0.2 mmol) and SM-4a (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dy was obtained as a yellow solid, yield: 42%.

¹H-NMR of the product 6dy (500 MHz, CDCl₃): δ 7.65-7.18 (m, 15H), 6.23 (m, 1H), 6.01 (m, 1H), 5.89 (m, 1H), 5.50 (m, 1H), 5.39 (m, 1H), 5.25 (m, 1H), 4.52 (m, 1H), 4.34 (m, 1H), 4.12 (m, 1H), 3.84 (m, 1H), 3.67 (s, 3H), 3.61 (s, 3H), 2.34-1.83 (m, 6H), 1.23 (d, 6H). ESI-MS [(M+H)⁺] for 6dy: m/z calculated 771.4. found 771.4.

EXAMPLE 114 Synthesis of Compound 6dz

Compound 6dz was prepared by the same coupling reaction procedure as in example 1, in which SM-3ck (0.2 mmol) and SM-4bf (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6dy was obtained as a yellow solid, yield: 38%.

¹H-NMR of the product 6dz (500 MHz, CDCl₃): δ 7.71-7.40 (m, 20H), 6.28 (m, 1H), 6.04 (m, 1H), 5.99 (m, 1H), 5.50 (m, 1H). 5.39 (m, 1H), 4.54 (m, 1H), 4.12 (m, 1H), 3.98 (m, 1H), 3.68 (s, 3H), 3.65 (s, 3H), 2.23-1.82 (m, 6H). ESI-MS [(M+H)⁺] for 6dz: m/z calculated 805.3. found 805.5.

EXAMPLE 115 Synthesis of Compound 6ea

Compound 6ea was prepared by the same coupling reaction procedure as in example 1, in which SM-3ay (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6ea was obtained as a yellow solid, yield: 33%.

¹H-NMR of the product 6ea (500 MHz, CDCl₃): δ 7.67-7.20 (m, 13H), 6.26 (s, 1H), 6.15 (s, 1H), 6.08 (m, 1H), 5.99 (m, 1H), 5.59 (m, 1H), 5.46 (m, 1H), 5.31 (m, 1H), 4.76 (m, 1H), 4.48 (m, 1H), 4.30 (m, 1H), 3.70 (s, 3H), 3.65 (s, 3H), 3.22 (m, 1H), 2.24-1.92 (m, 6H), 1.26 (d, 6H). ESI-MS [(M+H)⁺] for 6ea: m/z calculated 771.4. found 771.5.

EXAMPLE 116 Synthesis of Compound 6eb

Compound 6eb was prepared by the same coupling reaction procedure as in example 1, in which SM-3bx (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6eb was obtained as a yellow solid, yield: 37%.

ESI-MS [(M+H)⁺] for 6eb: m/z calculated 737.4. found 737.4.

EXAMPLE 117 Synthesis of Compound 6ec

Compound 6eb was prepared by the same coupling reaction procedure as in example 1, in which SM-3by (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6ec (30 mg) was obtained as a yellow solid, yield: 43%.

ESI-MS [(M+H)⁺] for 6ec: m/z calculated 737.4. found 737.5.

EXAMPLE 118 Synthesis of Compound 6ej

Compound 6ej was prepared by the same coupling reaction procedure as in example 1, in which SM-3ci (0.2 mmol) and SM-4bd (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6ej (76 mg) was obtained as a yellow solid, yield: 43%.

ESI-MS [(M+H)⁺] for 6ej: m/z calculated 880.4. found 880.5.

EXAMPLE 119 Synthesis of Compound 6ek

Compound 6ek was prepared by the same coupling reaction procedure as in example 1, in which SM-3cq (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6ek (81 mg) was obtained as a yellow solid, yield: 46%.

ESI-MS [(M+H)⁺] for 6ek: m/z calculated 881.5. found 881.5.

EXAMPLE 120 Synthesis of Compound 6em

Compound 6em was prepared by the same coupling reaction procedure as in example 1, in which SM-3cq (0.2 mmol) and SM-4bf (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6em (75 mg) was obtained as a yellow solid, yield: 41%.

ESI-MS [(M+H)⁺] for 6em: m/z calculated 915.5. found 915.5.

EXAMPLE 121 Synthesis of Compound 6en

Compound 6en was prepared by the same coupling reaction procedure as in example 1, in which SM-3cr (0.2 mmol) and SM-4bg (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6en (94 mg) was obtained as a yellow solid, yield: 54%.

ESI-MS [(M+H)⁺] for 6en: m/z calculated 869.5. found 869.5.

EXAMPLE 122 Synthesis of Compound 6ep

Compound 6ep was prepared by the same coupling reaction procedure as in example 1, in which SM-3by (0.2 mmol) and SM-4b (0.2 mmol) were used instead of SM-3a and SM-4i, and the product 6ep (71 mg) was obtained as a yellow solid, yield: 39%.

ESI-MS [(M+H)⁺] for 6ej: m/z calculated 903.5. found 903.5.

EXAMPLE 123 Synthesis of Compound 6fa

Compound 6fa was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3au (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fa was obtained (105 mg, yield: 53%).

Confirmed by MS, ESI-MS [(M+H)⁺] for 6fa: m/z calculated 991.3. founded 991.4.

EXAMPLE 124 Synthesis of Compound 6fb

Compound 6fb was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3av (0.2 mmol) and SM-4ad (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fb was obtained (98 mg, yield: 47%).

Confirmed by MS, ESI-MS [(M+H)⁺] for 6fb: m/z calculated 1025.3. founded 1025.4.

EXAMPLE 125 Synthesis of Compound 6fc

Compound 6fc was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ba (0.2 mmol) and SM-4ah (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fc was obtained (87 mg, yield: 52%).

Confirmed by MS. ESI-MS [(M+H)⁺] for 6fc: m/z calculated 833.3. founded 833.4.

EXAMPLE 126 Synthesis of Compound 6fd

Compound 6fd was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3av (0.2 mmol) and SM-4ah (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fd was obtained (83 mg, yield: 48%).

Confirmed by MS, ESI-MS [(M+H)⁺] for 6fd: m/z calculated 867.2. founded 867.3.

EXAMPLE 127 Synthesis of Compound 6fe

Compound 6fe was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3aw (0.2 mmol) and SM-4ah (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fe was obtained (95 mg, yield: 54%).

Confirmed by MS. ESI-MS [(M+H)⁺] for 6fe: m/z calculated 865.2. founded 865.3.

EXAMPLE 128 Synthesis of Compound 6ff

Compound 6ff was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cb (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6ff was obtained (69 mg, yield: 43%).

Confirmed by MS, ESI-MS [(M+H)⁺] for 6ff: m/z calculated 865.3. founded 865.3.

EXAMPLE 129 Synthesis of Compound 6fg

Compound 6fg was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cn (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fg was obtained (32 mg, yield: 20%).

¹H NMR for the product 6fg (500 MHz, CDCl₃): δ 7.39-7.10 (m, 8H), 6.09 (s, 1H), 5.99 (s, 1H), 5.49 (s, 1H), 5.25 (s, 1H), 4.74 (m, 1H), 4.38 (m, 1H), 4.32 (m, 1H), 3.91 (s, 1H), 3.71 (s, 6H), 2.38 (m, 2H), 2.19 (m, 2H), 2.09-2.07 (m, 4H), 1.28 (s, 6H), 1.27 (s, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6fg: m/z calculated 799.3. founded 799.3.

EXAMPLE 130 Synthesis of Compound 6fh

Compound 6th was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cm (0.2 mmol) and SM-4bf (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fh was obtained (46 mg, yield: 26%).

¹H NMR for the product 6fh (500 MHz, CDCl₃): δ 7.92-7.27 (m, 18H). 6.24 (s, 1H), 6.19 (s, 1H), 5.97 (s, 1H), 5.89 (s, 1H), 5.48 (m, 1H), 5.28 (s, 1H), 4.55 (m, 1H), 4.10 (s, 1H), 3.76 (s, 6H), 2.32-2.03 (m, 6H). Confirmed by MS. ESI-MS [(M+H)⁺] for 6fh: m/z calculated 867.3. founded 867.3.

EXAMPLE 131 Synthesis of Compound 6fi

Compound 6fi was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cm (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fi was obtained (59 mg, yield: 25%).

¹H NMR for the product 6fi (500 MHz, CDCl₃): δ 7.46-7.41 (m, 13H), 6.20 (s, 1H), 6.09 (s, 1H), 5.99 (s, 1H), 5.51 (m, 1H), 5.31 (m, 1H), 4.78 (m, 1H), 4.57 (m, 1H), 4.31 (m, 1H), 3.70 (s, 6H), 3.24 (m, 1H), 2.24-1.92 (m, 6H), 1.28 (s, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6fi: m/z calculated 833.3. founded 833.3.

EXAMPLE 132 Synthesis of Compound 6fj

Compound 6fj was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cn (0.2 mmol) and SM-4bf (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fj was obtained (53 mg, yield: 35%).

¹H NMR for the product 6fj (500 MHz, CDCl₃): δ 7.47-7.32 (m, 13H), 6.16 (s, 1H), 5.98 (s, 1H), 5.92 (s, 1H), 5.53 (m, 1H), 5.47 (m, 1H), 5.23 (m, 1H), 4.61 (m, 1H), 4.37 (m, 1H), 3.88 (m, 1H), 3.74 (s, 6H), 2.34-2.03 (m, 6H), 1.27 (s, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6fj: m/z calculated 833.3. founded 833.3.

EXAMPLE 133 Synthesis of Compound 6fk

Compound 6fk was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cp (0.2 mmol) and SM-4be (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fk was obtained (40 mg, yield: 26%).

¹H NMR for the product 6fk (500 MHz, CDCl₃): δ 7.46-7.31 (m, 18H). 6.27 (s, 1H), 6.12 (s, 1H), 5.99 (s, 1H), 5.90 (s, 1H), 5.52 (m, 1H), 5.33 (s, 1H), 4.53 (m, 1H), 4.11 (s, 1H), 3.69 (s, 6H), 2.34-1.99 (m, 6H). Confirmed by MS. ESI-MS [(M+H)⁺] for 6fk: m/z calculated 867.3. founded 867.3.

EXAMPLE 134 Synthesis of Compound 6fm

Compound 6fm was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cp (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fm was obtained (81 mg, yield: 48%).

¹H NMR for the product 6fm (500 MHz, CDCl₃): δ 7.47-7.40 (m, 13H), 6.24 (s, 1H), 5.97 (s, 1H), 5.90 (s, 1H), 5.58 (m, 1H), 5.27 (s, 1H), 4.62 (m, 1H), 4.36 (m, 1H), 4.12 (m, 1H), 3.88 (m, 1H), 3.73 (s, 6H), 2.18-2.02 (m, 6H), 1.26 (s, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6fm: m/z calculated 833.3. founded 833.3.

EXAMPLE 135 Synthesis of Compound 6fn

Compound 6fn was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cb (0.2 mmol) and SM-4a (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fn was obtained (63 mg, yield: 38%).

¹H NMR for the product 6fn (500 MHz, CDCl₃): δ 7.55-7.13 (m, 8H), 6.07 (s, 1H), 5.98 (s, 1H), 5.57 (s, 1H), 5.28 (s, 1H), 4.79 (m, 1H), 4.60 (m, 1H), 4.39 (m, 1H), 4.33 (s, 1H), 3.73 (s, 6H), 2.39 (m, 1H), 2.25 (m, 1H), 2.11-2.07 (m, 6H), 1.07 (s, 6H), 0.94 (s, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6fn: m/z calculated 799.3. founded 799.3.

EXAMPLE 136 Synthesis of Compound 6fp

Compound 6fp was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cb (0.2 mmol) and SM-4be (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fp was obtained (59 mg, yield: 35%).

¹H NMR for the product 6fp (500 MHz, CDCl₃): δ 7.45-7.39 (m, 13H). 6.18 (s, 1H), 6.06 (s, 1H), 5.95 (s, 1H), 5.61 (m, 1H), 5.30 (m, 1H), 4.77 (m, 1H), 4.56 (m, 1H), 4.30 (m, 1H), 3.70 (s, 3H), 3.63 (s, 3H), 3.22 (s. 1H), 2.25-1.91 (m, 6H), 1.26 (s, 6H). Confirmed by MS.

ESI-MS [(M+H)⁺] for 6fp: m/z calculated 833.3. founded 833.3.

EXAMPLE 137 Synthesis of Compound 6fq

Compound 6fq was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ce (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fq was obtained (61 mg, yield: 37%).

Confirmed by MS, ESI-MS [(M+H)⁺] for 6fq: m/z calculated 799.3. founded 799.4.

EXAMPLE 138 Synthesis of Compound 6fr

Compound 6fr was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cc (0.2 mmol) and SM-4bf (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fr was obtained (59 mg, yield: 35%).

Confirmed by MS, ESI-MS [(M+H)⁺] for 6fr: m/z calculated 833.3. founded 833.3.

EXAMPLE 139 Synthesis of Compound 6fs

Compound 6fs was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cd (0.2 mmol) and SM-4bf (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fs was obtained (57 mg, yield: 32%).

Confirmed by MS. ESI-MS [(M+H)⁺] for 6fs: m/z calculated 867.3. founded 867.5.

EXAMPLE 140 Synthesis of Compound 6 ft

Compound 6 ft was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cd (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6 ft was obtained (57 mg, yield: 34%).

¹H NMR for the product 6 ft (500 MHz, CDCl₃): δ 7.20-7.66 (m, 13H), 5.99-6.26 (m, 3H), 5.56-5.58 (m, 1H), 5.31-5.32 (m, 1H), 4.73-4.76 (m, 2H), 4.49-4.51 (m, 1H), 3.79-3.82 (m, 2H), 3.68-3.71 (m, 5H), 3.54 (s, 3H), 1.93-2.04 (m, 5H). 0.90-0.91 (m, 6H). Confirmed by MS, ESI-MS [(M+H)⁺] for 6 ft: m/z calculated 833.3. founded 833.5.

EXAMPLE 141 Synthesis of Compound 6fu

Compound 6fu was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ce (0.2 mmol) and SM-4bf (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fu was obtained (60 mg, yield: 37%).

Confirmed by MS, ESI-MS [(M+H)⁺] for 6fu: m/z calculated 817.3. founded 817.3.

EXAMPLE 142 Synthesis of Compound 6fv

Compound 6fv was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cf (0.2 mmol) and SM-4b (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fv was obtained (52 mg, yield: 32%).

Confirmed by MS, ESI-MS [(M+H)⁺] for 6fv: m/z calculated 817.3. founded 817.3.

EXAMPLE 143 Synthesis of Compound 6fw

Compound 6fw was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cf (0.2 mmol) and SM-4bf (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fw was obtained (55 mg, yield: 32%).

Confirmed by MS. ESI-MS [(M+H)⁺] for 6fw: m/z calculated 851.3. founded 851.3.

EXAMPLE 144 Synthesis of Compound 6fx

Compound 6fx was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cg (0.2 mmol) and SM-4bf (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fx was obtained (67 mg, yield: 39%).

Confirmed by MS, ESI-MS [(M+H)⁺] for 6fx: m/z calculated 850.3. founded 850.4.

EXAMPLE 145 Synthesis of Compound 6fy

Compound 6fy was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3ch (0.2 mmol) and SM-4be (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid 6fy was obtained (198 mg, yield: 48%).

Confirmed by MS. ESI-MS [(M+H)⁺] for 6fy: m/z calculated 833.3. founded 833.4.

EXAMPLE 146 Synthesis of Compound Ref-3

Compound Ref-3 was prepared by the same coupling reaction procedure as in example 1. By using the reagent SM-3cm (0.2 mmol) and SM-4be (0.2 mmol) instead of SM-3a and SM-4i, a yellow solid Ref-3 was obtained (69 mg, yield: 40%).

¹H NMR for the product Ref-3 (500 MHz, CDCl₃): δ 10.53 (s, 1H), 7.75-7.14 (m, 17H), 6.13 (m, 2H), 5.46 (m, 2H), 5.31 (m, 2H), 3.80 (m, 6H), 3.23 (m, 2H), 2.91 (m, 2H), 2.23-1.67 (m, 12H). Confirmed by MS, ESI-MS [(M+H)⁺] for Ref-3: m/z calculated 869.3. founded 869.3. 

1-40. (canceled)
 41. A compound represented by the formula Ia, or a stereoisomer, tautomer, esterification or amidation prodrug or pharmaceutically acceptable salt thereof:

wherein: m=1, 2 or 3; n=1, 2or 3; each dashed line “

” is, independently, a single bond or double bond, wherein when the dashed line connecting D to the adjacent carbon atom is a single bond, D is selected from the group consisting of O, S, N(Ra), CH₂, CH(OH), and C(Rb)(Rc), wherein when the dashed line connecting D to the adjacent carbon atom is a double bond, D is selected from the group consisting of N, CH, and C(Rb), wherein when the dashed line connecting D¹ to the adjacent carbon atom is a single bond, D¹ is selected from the group consisting of O, S, N(Ra), CH₂, CH(OH), and C(Rb)(Rc), and wherein when the dashed line connecting D¹ to the adjacent carbon atom is a double bond, D¹ is selected from the group consisting of N, CH, and C(Rb); Ra is H, hydroxyl, C₁-C₂₀ alkyl, C₁-C₂₀ cycloalkyl, C₆-C₂₀ aryl, C₂-C₂₀ heteroaryl, C₁-C₂₀ alkoxycarbonyl, C₃-C₂₀ cycloalkyloxycarbonyl, C₆-C₂₀ aryloxycarbonyl, C₂-C₂₀ heterocyclo-oxycarbonyl, C₁-C₂₀ alkylaminocarbonyl, C₃-C₂₀ cycloalkylamino-carbonyl, C₁-C₂₀ alkylamino sulfonamido, C₂-C₂₀ heterocyclo-aminosulfonyl, or C₆-C₂₀ arylaminosulfonyl; Rb and Rc are each, independently, selected from the group consisting of H, halogen, hydroxy, cyano, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₂-C₂₀ heterocyclo, C₆-C₂₀ aryl, C₁-C₂₀ alkoxy, C₁-C₂₀ alkylthio, C₁-C₂₀ alkoxycarbonyl, C₆-C₂₀ aryloxy, C₆-C₂₀ hetcroaryloxy, C₆-C₂₀ fused aryloxy, C₆-C₂₀ fused heterocyclo-oxy, C₆-C₂₀ aryloxycarbonyl, C₂-C₂₀ heterocyclo oxycarbonyl, C₂-C₂₀ heteroaryl, C₁-C₂₀ alkylamino, C₂-C₂₀ heterocycloamino, C₆-C₂₀ arylamino, C₁-C₂₀ alkylaminocarbonyl, C₁-C₂ alkylcarbonylamino, C₁-C₂₀ alkylsulfonamido, C₂-C₂₀ heterocyclosulfonamido, C₆-C₂₀ arylsulfonamido, and C₁-C₂₀ alkylaminosulfonamido; or Rb and Rc is linked to form a C₂-C₂₀ cycloalkyl, C₂-C₂₀ cycloalkenyl, or C₁-C₂₀ cycloethereal group; Ar, Ar¹ and Ar² are each, independently, selected from the group consisting of C₆-C₂₀ aryl, C₂-C₂₀ heteroaryl, C₈-C₂₀ fused aryl, and C₄-C₂₀ fused heteroaryl, or Ar and Ar¹ or Ar¹ and Ar² are linked each other to form C₁₀-C₂₀ fused alkylaryl or C₈-C₂₀ aryl group, or Ar¹ or Ar² does not exist and the groups bonded to Ar¹ or Ar² are directly linked; E and G are each, independently, selected from the group consisting of N, CH and C(Rb); wherein the definition of Rb is the same as the Rb in D and D¹ above; L and L¹ are each, independently, linked with D and/or D1, selected from the group consisting of O, S, N(Ra), C(═O), C(═O)O, C(═S)O, and C(═O)N(Ra), wherein the definition of Ra is the same as the Ra in D and D1 above; or L and/or L¹ are not present; Q and Q¹ are each, independently, selected from the group consisting of C₁-C₂₀ alkyl, C₁-C₂₀ alkoxy, C₁-C₂₀ alkylamino, C₃-C₂₀ cycloalkylamino, C₆-C₂₀ aryl, C₃-C₂₀ heteroaryl, C₃-C₂₀ poly-heteroaryl, C₃-C₂₀ fused aryl, and C₃-C₂₀ heteroaryl group, wherein when L and/or L¹ is not present, Q and/or Q¹ is not present; W and W¹ are each, independently, selected from the group consisting of carbonyl, thiocarbonyl, C₁-C₂₀ alkyl, C₆-C₂₀ aryl, and C₂-C₂₀ heteroaryl group; W² and W³ are each, independently, selected from the group consisting of carbonyl, thiocarbonyl, sulfonyl, C₁-C₂₀ alkyl, C₂-C₂₀ heterocyclo, C₆-C₂₀ aryl, and C₂-C₂₀ heteroaryl group; Z and Z¹ are each, independently, selected from the group consisting of H, hydroxy, amino, C₁-C₂₀alkyl, C₃-C₂₀ cycloalkyl, C₁-C₂₀alkoxy, C₁-C₂₀ cycloalkyl-oxy, C₁-C₂₀ alkylamino, C₃-C₂₀ cycloalkylamino, C₂-C₂₀ heterocyclo, C₂-C₂₀ heterocycloamino, C₆-C₂₀ aryl, C₆-C₂₀ aryloxy, C₆-C₂₀ arylamino, C₃-C₂₀ heteroaryloxy, C₃-C₂₀ heteroarylamino, C₁-C₂₀ alkylsulfonamido, C₃-C₂₀ cycloalkylsulfonamido, C₆-C₂₀ arylsulfonamido, C₁-C₂₀ alkoxysulfonamido, C₃-C₂₀ cycloalkyloxy-sulfonamido, C₆-C₂₀ aryloxysulfonamido, C₁-C₂₀ alkylaminosulfonamido, C₃-C₂₀ cycloalkylaminosulfonamido, and C₆-C₂₀ arylaminosulfonamido group; R¹, R², R³ and R⁴ are each, independently, selected from the group consisting of H, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₂-C₂₀ heterocyclo, C₆-C₂₀ aryl, C₂-C₂₀ heteroaryl, C₁-C₂₀ alkoxycarbonyl, C₆-C₂₀ aryloxycarbonyl, C₂-C₂₀ heterocyclo-oxy carbonyl, C₁-C₂₀ alkylaminocarbonyl, C₁-C₂₀ alkylaminosulfonamido, C₂-C₂₀ heterocycloaminosulfonyl, and C₆-C₂₀ arylaminosulfonyl group; and R⁵, R⁶, R⁷ and R⁸ are each, independently, selected from the group consisting of H, halogen, hydroxy, cyano, amino, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₂-C₂₀ heterocyclo, C₁-C₂₀ alkoxy, C₁-C₂₀ alkylamino, C₂-C₂₀ heterocycloamino, C₆-C₂₀ aryl, C₃-C₂₀heteroaryl, C₆-C₂₀ arylamino, C₁-C₂₀ alkoxycarbonylamino, C₁-C₂₀ alkylaminocarbonylamino, C₁-C₂₀ alkylsulfonamido, C₂-C₂₀ heterocyclosulfonamido, C₆-C₂₀ arylsulfonamido, and C₁-C₂₀ alkylaminosulfonamido, or R⁵ and R⁶ are linked to each other to form a cyclo group, or R⁷ and R⁸ are linked to each other to form a cyclo group.
 42. The compound according to claim 41, wherein m=1 or 2 and n=1 or
 2. 43. The compound according to claim 41, wherein the dashed line “

” is double bond and D and/or D¹ are CH.
 44. The compound according to claim 41, wherein the dashed line “

” is single bond; D and D¹ are each, independently, selected from the group consisting of O, S, N(Ra), CH₂, CH(OH) and C(Rb)(Rc); Ra is H, hydroxy, C₁-C₁₂ alkyl, C₁-C₁₂ cycloalkyl, C₆-C₁₂ aryl, C₂-C₁₂ heteroaryl, C₁-C₁₂ alkoxycarbonyl, C₃-C₁₂ cycloalkyloxycarbonyl, C₆-C₁₂ aryloxycarbonyl, C₂-C₁₂ heterocyclo-oxycarbonyl, C₁-C₁₂ alkylaminocarbonyl, C₃-C₁₂ cycloalkylaminocarbonyl, C₁-C₁₂ alkylaminosulfonamido, C₂-C₁₂ heterocycloaminosulfonyl, or C₆-C₁₂ arylaminosulfonyl; and Rb and Rc are each, independently, selected from the group consisting of H, halogen, hydroxy, cyano, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₂-C₁₂ heterocyclo, C₆-C₁₂ aryl, C₁-C₁₂ alkoxy, C₁-C₁₂ alkylthio, C₁-C₁₂ alkoxycarbonyl, C₆-C₁₂ aryloxy, C₆-C₁₂ heteroaryloxy, C₆-C₁₂ fused aryloxy, C₆-C₁₂fused heterocyclo-oxy, C₆-C₁₂ aryloxycarbonyl, C₂-C₁₂ heterocyclo oxycarbonyl, C₂-C₁₂ heteroaryl, C₁-C₁₂ alkylamino, C₂-C₁₂ heterocycloamino, C₆-C₁₂ arylamino, C₁-C₁₂ alkylaminocarbonyl, C₁-C₁₂ alkylcarbonylamino, C₁-C₁₂ alkylsulfonamido, C₂-C₁₂ heterocyclosulfonamido, C₆-C₁₂ arylsulfonamido, C₁-C₁₂alkylaminosulfonamido; or Rb and Rc are linked to form C₂-C₁₂ cycloalkyl, C₂-C₁₂ cycloalkenyl, or C₁-C₁₂ cycloethereal group.
 45. The compound according to claim 44, wherein the dashed line “

” is single bond; the D and/or D¹ is each O, N(Ra), CH₂, CH(OH) or C(Rb)(Rc), wherein Ra is H, hydroxy, C₁-C₅ alkoxycarbonyl, C₃-C₆ cycloalkyloxycarbonyl, C₃-C₁₀ cycloalkylaminocarbonyl, C₁-C₄ alkylaminosulfonamido, or C₂-C₁₀ heterocycloaminosulfonyl group; and Rb and Rc are linked to form C₂-C₅ cycloalkyl, or C₁-C₂ cycloethereal group.
 46. The compound according to claim 41, wherein Ar, Ar¹, Ar² and Ar³ are each, independently, selected from the group consisting of C₆-C₁₂aryl, C₂-C₁₂ heteroaryl, C₈-C₁₂ fused aryl, and C₄-C₁₂ fused heteroaryl, or Ar and Ar¹ or Ar¹ and Ar² are linked each other to form C₁₀-C₁₂ fused alkylaryl or C₈-C₁₂ aryl group, or Ar¹ or Ar² does not exist and the groups bonded to Ar¹ or Ar² are directly linked.
 47. The compound according to claim 46, wherein Ar and Ar¹ are each selected from

or the Ar and Ar¹ are linked each other as a fused aryl or heteroaryl group represented by the structure

and Ar² and Ar³ are

respectively.
 48. The compound according to claim 41, wherein E is N, and G is CH.
 49. The compound according to claim 41, wherein L and/or L¹ is selected from the group consisting of O, NH, or L and/or L¹ does not exist.
 50. The compound according to claim 41, wherein Q and/or Q¹ are each, independently, selected from the group consisting of C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, C₁-C₁₂ alkylamino, C₃-C₁₂ cycloalkylamino, C₆-C₁₂ aryl, C₃-C₁₂ heteroaryl, C₃-C₁₂ poly-heteroaryl, C₃-C₁₂ fused aryl, and C₃-C₁₂ heteroaryl group, wherein when the L and/or L¹ does not exist, Q and/or Q¹ does not exist.
 51. The compound according to claim 50, wherein Q and/or Q¹ is independently represented by one the following structures:


52. The compound according to claim 41, wherein W and W¹ are each, independently, selected from the group consisting of carbonyl, thiocarbonyl, C₁-C₁₂ alkyl, C₆-C₁₂ aryl, and C₂-C₁₂ heteroaryl group.
 53. The compound according to claim 52, wherein W and W¹ are each a carbonyl group.
 54. The compound according to claim 41, wherein W² and W³ are each, independently, selected from the group consisting of a carbonyl, thiocarbonyl, sulfonyl, C₁-C₁₂ alkyl, C₂-C₁₂ heterocyclo, C₆-C₁₂ aryl, and C₂-C₁₂ heteroaryl group.
 55. The compound according to claim 54, wherein W² and W³ are each a carbonyl group.
 56. The compound according to claim 41, wherein Z and Z¹ are each, independently, selected from the group consisting of H, hydroxy, amino, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₁-C₁₂ alkoxy, C₃-C₁₂ cycloalkyl-oxy, C₁-C₁₂ alkylamino, C₃-C₁₂ cycloalkylamino, C₂-C₁₂ heterocyclo, C₂-C₁₂ heterocycloamino, C₆-C₁₂ aryl, C₆-C₁₂ aryloxy, C₆-C₁₂ arylamino, C₃-C₁₂ heteroaryloxy, C₃-C₁₂ heteroarylamino, C₁-C₁₂ alkylsulfonamido, C₃-C₁₂ cycloalkylsulfonamido, C₆-C₁₂ arylsulfonamido, C₁-C₁₂ alkoxysulfonamido, C₃-C₁₂ cycloalkyl-oxy-sulfonamido, C₆-C₁₂ aryloxysulfonamido, C₁-C₁₂ alkylaminosulfonamido, C₃-C₁₂ cycloalkylaminosulfonamido, and C₆-C₁₂ arylaminosulfonamido group.
 57. The compound according to claim 56, wherein Z and Z¹ are C₁-C₁₂ alkoxy, or C₁-C₁₂ alkylamino group.
 58. The compound according to claim 41, wherein R¹, R², R³ and R⁴ are each, independently, selected from the group consisting of H, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₂-C₁₂ heterocyclo, C₆-C₁₂ aryl, C₂-C₁₂ heteroaryl, C₁-C₁₂ alkoxycarbonyl, C₆-C₁₂ aryloxycarbonyl, C₂-C₁₂ heterocyclo-oxy carbonyl, C₁-C₁₂ alkylaminocarbonyl, C₁-C₁₂ alkylaminosulfonamido, C₂-C₁₂ heterocycloaminosulfonyl, and C₆-C₁₂ arylaminosulfonyl group.
 59. The compound according to claim 58, wherein R¹ does not exist, R² is H, R³ is H, and R⁴ is H.
 60. The compound according to claim 41, wherein R⁵, R⁶, R⁷ and R⁸ are each, independently, selected from the group consisting of H, halogen, hydroxy, cyano, amino, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₂-C₁₂ heterocyclo, C₁-C₁₂ alkoxy, C₁-C₁₂ alkylamino, C₂-C₁₂ heterocycloamino, C₆-C₁₂ aryl, C₆-C₁₂ arylamino, C₁-C₁₂ alkoxycarbonylamino, C₁-C₁₂ alkylaminocarbonylamino, C₁-C₁₂ alkylsulfonamido, C₂-C₁₂ heterocyclosulfonamido, C₆-C₂ arylsulfonamido, and C₁-C₁₂ alkylaminosulfonamido, or R⁵ and R⁶ are linked to form a cyclo group, or R⁷ and R⁸ are linked to each other to form a cyclo group.
 61. The compound according to claim 60, wherein R⁵ and R⁷ are H; and R⁶ and R⁸ are a C₁-C₆ alkyl, C₂-C₆ heterocyclo, C₆-C₁₀ aryl, or C₃-C₈ heteroaryl group.
 62. The compound according to claim 41, which is represented by one of the following structures:


63. A pharmaceutical composition, comprising the compound according to claim 41 and a pharmaceutically acceptable carrier.
 64. A composition, comprising at least one compound according to claim 41 and at least one compound selected from the group consisting of an HIV inhibitor and a hepatitis B virus (HBV) inhibitor.
 65. A composition, comprising at least one compound according to claim 41 and at least one compound selected from the group consisting of Lamivudine, Telbivudine, Adefovir, Entecavir, Tenofovir and Clevudine.
 66. A composition, comprising at least one compound according to claim 41 and at least one compound selected from the group consisting of (1) Immune modulators, (2) HCV protease inhibitors, (3) HCV polymerase inhibitors, (4) nucleosides and derivatives thereof, (5) Cyclophilin inhibitors, (6) Glucosidase I inhibitors, (7) IMPDH inhibitors, (8) Caspase inhibitors, (9) TLR agonists, (10) HIV inhibitors, (11) anti-inflammatory drugs, and (12) anti-cancer drugs.
 67. A method of inhibiting Hepatitis C virus comprising contacting Hepatitis C virus with an effective amount of the compound according to claim
 41. 68. A method of treating a subject infected with Hepatitis C virus comprising administering an effective amount of the compound according to claim 41 to the subject.
 69. A method of treating a subject infected with Hepatitis C virus comprising administering an effective amount of the composition according to claim 63 to the subject.
 70. A method of treating a subject infected with Hepatitis C virus comprising administering an effective amount of the composition according to claim 64 to the subject.
 71. A method of treating a subject infected with Hepatitis C virus comprising administering an effective amount of the composition according to claim 65 to the subject.
 72. A method of treating a subject infected with Hepatitis C virus comprising administering an effective amount of the composition according to claim 66 to the subject. 